HHS SBIR PHS 2012-1 1

Radiotherapy is employed in the treatment of over half of all cancer patients. Many of those patients however, may suffer some adverse effects from this therapy during and/or after treatment. In addition, in approximately half of the patients treated with curative intent, the tumors recur. Enhancing specific tumor killing and minimizing normal tissue damage from radiotherapy would improve tumor control and patient quality of life. An ideal intervention would enhance both radiation effects in tumors and protect the normal tissues.

Radiosensitizersare agents that are intended to enhance tumor cell killing while having a minimal effect on normal tissues. Recently, two new radiation sensitization drugs have proven clinically effective: Temozolomide treatment with radiotherapy for glioblastoma and Cetuximab treatment combined with radiation for head and neck squamous cell cancers. A large number of other targeted therapies are possible and although some are currently in varying phases of development, there is significant potential for further development of novel agents.

Conventionally, radioprotectors are defined as agents given before radiation exposure to prevent or reduce damage to normal tissues, while mitigators refer to those agents given during or after a patient’s prescribed course of radiation therapy to prevent or reduce imminent damage to normal tissues. Both radioprotectors and mitigators are also being developed as potential countermeasures against radiological terrorism and several have shown promise in pre-clinical testing. In order for these to be developed and useful in clinical radiation therapy applications it is imperative to demonstrate that they do not protect cancer cells.

The importance of developing agents that sensitize tumor cells, protect or mitigate radiation-induced damage in normal tissue, improve survival, quality of life, and palliative care in cancer patients was emphasized in a recent NCI workshop on Advanced Radiation Therapeutics - Radiation Injury Mitigation held on January 25th 2010 (2), and in a workshop on Radiation Resistance in Cancer Therapy: Its Molecular Bases and Role of the Microenvironment on its Expression held Sept 1-3, 2010. Prior workshops have dealt with sensitization, protection, or radiation effects assessment (3,4).

This contract topic aims to encourage the development of innovative and promising radioprotectants, mitigators, or sensitizers that either selectively protect normal tissues (but not tumors) against ionizing radiation or selectively sensitize tumors, thereby increasing the therapeutic ratio of radiation. Proposals for radiation modulators are solicited that include preclinical and/or early phase clinical studies demonstrating safety, efficacy, dose, schedule, pharmacokinetics (PK), pharmacodynamics (PD), and metabolism. Proposals should also demonstrate a clear understanding of regulatory requirements, and should include a regulatory plan including key steps such as a pre-IND meeting with FDA, submitting an investigational new drug (IND) application, approval of clinical trial design, and ultimately drug registration.

Project goals:

The goal is to stimulate collaborations among academic institutions, small businesses, and contract research organizations in order to promote the rapid development of innovative radioresponse modifiers that will decrease normal tissue injury and/or enhance tumor killing thereby improving radiotherapy outcomes. The long-term goal is to enable small businesses to fully develop, license, and/or market radioresponse modifiers for clinical use.

The contract proposal must describe:

Phase I:

·       A quantitative estimate of the patient population that will benefit from the availability of such radioresponse modifiers.

·       A plan for generating evidence that the proposed compound(s) protects at least one relevant normal tissue from radiation-induced injury, and/or sensitizes at least two relevant tumor models.

·       Either: 1) A plan for generating evidence that the proposed radioprotector(s)/mitigators(s) do not significantly protect cancer cells, or 2) A plan for generating evidence that the proposed radiosensitizer(s) do not significantly sensitize normal cells and tissues.

·       The plans must include the methodologies proposed to evaluate the preferential effects on normal tissues or tumors by the compound(s) in vivo (including appropriate biomarkers and endpoints as determined during early interactions with the FDA).

·       Determination of the optimum dose and schedule in vivo based upon preclinical pharmacodynamic and pharmacokinetic studies.

·       Statistical validation of the proposed study endpoints including where appropriate, power calculations and rationale for proposed sample sizes.

Phase II:

·       The approach to early-phase human trials, as indicated, that are designed taking into account the relevant molecular pathways and targets and aim to gather pharmacodynamic and pharmacokinetic data to confirm the compound’s observed behavior in animal studies.

·       The approach to assessing the safety and efficacy of the compound(s) in early-phase human trials employing, as appropriate, physician-reported endpoints as well as patient-reported outcomes.

Activities and ExpectedDeliverables:

Phase I may include primarily preclinical studies. Phase II or "Fast-Track" proposals must contain a section entitled "Regulatory Plan" detailing plans for early involvement of the FDA. There should be a description of how the applicant plans on meeting the requirements to: 1) define suitable biomarkers and endpoints, 2) file IND and 3) design and perform phase 0-2 clinical trials in preparation for product transition to phase 3 clinical trials by groups such as the RTOG. Where cooperation of other partners is critical for implementation of the proposed methodology, the applicant should provide evidence of such cooperation (through partnering arrangement, letters of support, etc.).

The following deliverables may be required depending on a compound’s maturity in the developmental pipeline:

Phase I:

·       Selection and approval of cell panels for in vitrotesting.

·       Demonstration of drug solubility and uptake using cultured normal and transformed cells.

·       Study design for determining clonogenic survival or approved alternative tailored to the mechanism of each tested compound.

·       Clonogenic survival data or approved alternative validating lack of drug toxicity in normal cells, efficacy and specificity of radioprotection for normal cells and/or efficacy and specificity of radiosensitization for tumor cells.

·       Preliminary evidence for lack of toxicity to normal tissue and/or lack of acute toxicities such as vomiting, hypotension etc , preferably demonstrated in vivo.

·       Documentation providing a top-level description of the protocols and the testing results should be provided to NCI as part of the Phase I progress report.

Phase II:

For advanced pre-clinical work:

·       Design of an NCI/institutional animal care and use committee approval of in vivo experimentation plan including statistical validation of experimental design/sample size including power calculations. In addition, selection and approval of tumor cell panel and normal tissues for in vitro testing.

·       Demonstration of bioavailability PK and PD in rodent model.

·       For radiation protectors / mitigators: demonstration by physiologic testing and histological assessment that irradiated normal tissues are spared over a 6-month period.

·       Demonstration of effects (sensitization or lack of protection as appropriate) on tumors using in vivo radiation regrowth delay assays.

·       Collection of data validating lack of drug toxicity, efficacy, and specificity for normal cells over tumor cells in the case of radiation protectors/mitigators.

For proposals advancing to early phase human trials:

·       Identify GMP drug source

·       Obtain IND approval

·       Provide evidence of established clinical collaboration

·       Submitted protocol for IRB approval

·       Define suitable clinical endpoints and patient-oriented outcomes.

Documentation of the testing protocol and testing results should be provided to NCI as part of the Phase II progressreportfor pre-clinical studies. 

The design of novel therapies and drug delivery systems for cancer is being enabled by nanotechnology. Nanoscale devices carrying therapeutic payloads and delivered within close proximity of the tumor in vivo will play a significant role in increasing the effectiveness of the treatment while decreasing severity of side effects. Such techniques would be highly relevant, particularly for organs that are difficult to access because of a variety of biological barriers, including those developed by tumors. The successful delivery of well established chemotherapeutics using nanoparticle-based delivery platforms has previously been demonstrated; however, an even bigger opportunity that can be enabled by nanoparticle delivery is the potential to mitigate the adverse properties of once promising drugs which failed to reach clinical trials or failed in clinical trials due to excessive toxicity and can be reformulated into safe and viable therapies using nanoparticles. Furthermore, poor oral bioavailability, poor solubility in biological fluids, inappropriate pharmacokinetics, and lack of efficacy within a tolerable dose range can be also addressed using such reformulation approaches.

To accelerate such efforts, the National Cancer Institute (NCI) requests proposals for the development of commercially-viable nanotechnology-based platforms for the reformulation of cancer therapeutics.

Project Goals:

The goal of this project is to identify and evaluate the potential of candidate nanotechnologies to significantly improve the performance of anti-cancer agents. Specifically, this topic is intended to fund nanotechnology delivery systems which will enable anti-cancer drugs which could not otherwise be delivered in free form due to their excessive toxicity, poor oral bioavailability, poor solubility in biological fluids, inappropriate pharmacokinetics, and lack of efficacy within a tolerable dose range to be re-examined as potential therapies for cancer treatment. Drug-nanoparticle constructs must yield a significant improvement in properties with respect to the free drug and FDA-approved formulations of the drug. Of special interest are drug-nanoparticle constructs which mitigate the unacceptable properties of the drugs which may not currently be administered to humans in free form.

These drug-nanoparticle constructs can take, for example, the form of multi-functional targeted nanoparticles or multi-chamber chips carrying encapsulated drugs. Further, the drug-nanoparticle constructs may also utilize imaging agents for a combination of therapeutic and diagnostic modalities that aim to provide real-time feedback and monitoring of therapy. They may include, but are not limited to the following:

·       novel therapeutic nanodevices

·       devices involving novel tumor targeting and concentrations schemes

·       novel drug loading and releasing schemes

·       novel therapeutic or theranostic nanodevices which are able to cross the blood-brain barrier

Offerors must identify the drug which they intend to reformulate for this topic. Offerors must also cite at least one clinical trial, one paper in a respected journal or submit original data which clearly demonstrates the reason(s) which prevented the drug from receiving FDA approval or entering clinical trials. Offerors must provide evidence that they can synthesize, purchase or otherwise obtain the drug as part of their proposal in order to be eligible for this topic (i.e., Offerors are solely responsible for obtaining the drug). Intellectual property issues and material transfer agreements regarding the usage of the drug are the responsibility of the offerors. Peptides, proteins and nucleic acids are not acceptable drug candidates for this topic.

Phase I Activities and Expected Deliverables:

·       Proof-of-conceptencapsulation or attachment of undeliverable therapeutic agent to nanoparticle

·       In vitrodemonstration of nanoconstruct stability and controlled release of therapeutic agent from nanoconstruct

·       Proof-of-concept in vitro studies demonstrating efficacy in relevant cell lines

·       Proof-of-concept small animalstudies demonstrating improved therapeutic efficacy and improved therapeutic index, bioavailability, solubility, and/or pharmacokinetics as compared to the use of free drug (utilizing an appropriate animal model)

Phase II Activities and Expected Deliverables:

·       Long Term Toxicity Studies

·       Biodistribution Studies

·       Initiation of large animal studies

·       Demonstration of nanotherapeutic manufacturing and scale-up scheme

IND-enabling studies carried out in a suitable pre-clinical environment

Biological fluids and tissue biopsies provide important information with respect to a diagnosis of cancer and to efficacy of its treatment. The collection of both (especially the biopsy) is invasive and can be achieved only in single time points with limited frequency. The analysis of biological fluids (blood, urine), which are easier to collect, do not provide for direct representation of the tumor development. It assesses the status of the tumor only on the basis of biomarkers which are given away by the tumor and release to the biological fluid. The release of these biomarkers and its close correlation to tumor growth varies from organ to organ and its kinetics is not well understood.

On the other hand, ability to monitor tumor microenvironment directly in vivo, in close proximity to the tumor site, will facilitate for a significant improvement in the collection of data (metabolite concentrations, biomarkers, enzymatic activity) associated with tumor growth and its behavior under treatment. It will also contribute to advancing out understanding of metastasis. Nanotechnology allows for the design and manufacture of complex multi-functional particles and devices which could yield temporal data for these important parameters in vivo. This could be achieved in several ways: 1) through the development of nanoparticles with surfaces or biological coatings which recognize parameters associated with tumor microenvironment where tumor-targeted particles are introduced systemically; 2) through the design of implantable biochemical sensors which can collect data over the extended period of time; 3) through the design of circulating nano-sensors which collect data while traveling in blood stream and then are excreted from the body for further evaluation.

To accelerate such efforts, the National Cancer Institute (NCI) requests proposals for the development of commercially-viable nanotechnology-based diagnostic platforms capable of monitoring tumor microenvironment in vivo.

Project Goals:

The goal of the project is to develop nano-enabled in vivo diagnostic platforms that can provide increased sensitivity and specificity in detecting cancer or cancer metastasis or monitoring effectiveness of the treatment in pre-clinical animal models of cancer and/or in human patients. These capabilities will offer clinicians a way to maximize opportunities for early disease recognition and produce positive clinical outcomes.

Potential relevant sensing nanoplatforms could include, but are not limited to:

Nano-enabled Sensing Platforms for In Vivo Applications

Examples: Several different design modalities can be considered: 1) use of nanoparticles which are introduced systemically or locally and possess surfaces or biological coatings which recognize parameters associated with tumor microenvironment and report their change (through the change of electrical, optical, magnetic signal); 2) use of biochemical sensors which are implanted and can collect data over the extended period of time; 3) use of systemically introduced nanoparticles or nanodevices which collect the data and subsequently are excreted for further evaluation.

Potential Applications: Diagnosis of cancer or cancer metastasis or long-term monitoring of treatment effectiveness based on biochemical markers or CTCs or other physiological indicators such as pH or oxygen level.

Given the diversity of potential applications discussed above, submitted proposals should place emphasis on the specific nanotechnology-enabling component of the proposed platform.

Phase I Activitiesand Expected Deliverables:

·       Design describing:

o   unique in vivo sensing capabilities enabled by nanotechnology

o   proof of concept experiments

o   benchmarkingexperiments against conventional methodologies

·       First-stage validation of design in relevant preclinical samples

o   Demonstrate 1) the recognition of relevant clinical biomarkers or other tumor microenvironment indicators by nanoparticles or nanodevices incubated in blood, urine, or other biological fluids in vitro at varied concentrations and concentration profiles, and 2) isolation of nanoparticles from the biological fluid

·       Successful completion of benchmarking experiments demonstrating a minimum of 5x improvement against conventional methodologies

Phase II Activities and Expected Deliverables:

·       Second-stage validation of design for potential clinical adaptation

o   Demonstrate the recognition of relevant clinical biomarkers or other tumor microenvironment indicators by nanoparticles or nanodevices in relevant animals models including large animals

·       Systematic study of sensitivity and specificity of the sensor platform in pre-clinical or clinical samples and demonstrate reproducibility

·       Collect data from a statistically significant number of animals or patients in preparation for an IDE application

·       Submit IDE application to obtain necessary regulatory approval for clinical validation

Image processing algorithms are increasingly important as imaging and image-guided intervention technologies become critical in screening, diagnosis, staging, treatment and monitoring of cancer patients. The use of in vivo imaging modalities such as MRI, X-ray, CT, Positron Emission Tomography, Nuclear Medicine, Ultrasound, Optical Coherence Tomography, and Photo-acoustic imaging, as well as multi-modality imaging for the management of cancer patients has continued to increase exponentially. As more and more imaging data becomes available, innovative software algorithms for image processing and analysis will be a critical need for effective use of the information presented by medical images.

Improved image processing and analysis software serves the needs of cancer patients by enhancing the ability to distinguish viable cancer from necrotic cells, or swelling, or other benign causes of persistent radiographic abnormalities. Advanced software also allows the radiologist to detect cancer earlier, when treatments may be more effective, and to perform a non-invasive or image-guided needle biopsy approach to diagnose cancer and avoid an open surgical procedure. In many cases, advanced visualization and post processing algorithms enable faster and more accurate assessment of disease extent to guide treatment options, at the time of diagnosis and during treatment.

Project goals:

The short-term goal of this topic is to develop robust algorithms to enable faster and more accurate decision making for imaging and image-guided interventions. These include but are not limited to the following:

·       Algorithms that enable real-time reconstruction and display of images for image-guided interventions.

·       Extraction of clinically relevant quantitative information from images.

·       Improvements in multimodality image co-registration, image fusion and deformable models for image visualization and image-guided interventions.

·       Optimization in image processing techniques that enhance visualization (e.g. segmentation tools, noise reduction etc) and facilitates image analysis.

·       Novel methods for feature extraction, object recognition to develop tools for computer-aided detection (CAD) and monitor changes over time.

·       Algorithms to process large image data sets quickly.

Development of algorithms for image acquisition and/or routine image processing for a new medical imaging device is not appropriate for this solicitation and should not be submitted. Image processing algorithms that are vendor independent and can be applied to multiple modalities are strongly encouraged by the NCI. However, this does not exclude the possibility that future commercialization may be executed initially through a single vendor.

It is expected that the proposed innovation will be driven by clinical practice. Therefore, in addition to standard proposal components; the contract proposal must contain specific discussion of the target patient population and evidence of an existing clinical problem which is addressed by the proposed method. The proposal must also contain an analysis of competitive methods to address the same problem and explanation of competitive technical advantages of proposed algorithm. All Phase II or Fast-Track proposals MUST contain a section entitled “Regulatory Plan” that demonstrates an understanding of the regulatory requirements for clearing the software device through the FDA, details the company’s plan to meet the requirements, and explains how the proposed work helps to meet these requirements. If regulatory approval is not expected to be required, the offeror must provide an extensive justification for this.

The long-term goal of the program is to create software packages with novel algorithms that can be integrated into one or more different commercial imaging platforms, where appropriate.

Applicants are encouraged to explore affiliations with the NCI Research Networks such as the Quantitative Imaging Network (QIN) (http://grants.nih.gov/grants/guide/pa-files/PAR-08-225.html) which aims to develop a consensus on methods to validate software and modeling methods , share ideas and approaches to validate and standardize imaging data and related imaging metadata for quantitative measurements of responses to cancer therapies.

Phase I Activitiesand Expected Deliverables:

·       Development of an innovative algorithm to improve image processing methods for imaging or image-guidedinterventions for cancer patients.

·       Preliminaryvalidation of the algorithms in phantoms or clinical patient image data-sets, as appropriate. The NCI Cancer Imaging Program has a link to publically available resources for digital image data-sets: (http://imaging.cancer.gov/programsandresources/InformationSystems/ImageArchiveResources/page14).

·       In-personsoftware demonstration to NCI Program staff (travel to NCI must be included in the budget).

·       Final progressreport should include plans for distribution of the product as part of the commercialization objectives. If co-operation of other companies or large equipment manufacturers is required for commercialization, provide evidence of established communication with potential partners.

Phase II Activities and Expected Deliverables:

·       Establishmentof an FDA-compliant Quality System for software development.

·       Productionof a clinic ready software package with user-friendly graphical user interface.

·       Extensiveclinical validation using reader studies with prospective data to demonstrate improvements from the developed algorithms including usability as compared to current standard of care.

·       Draft usermanual.

·       Provide Standard Operating Procedure for clinic-ready software to NCI.

·       Present finalresults to NCI.

Medical imaging plays a key role in clinical management of cancer patients. Cancer imaging agents are used in conjunction with medical imaging equipment, and, by highlighting the contrast between normal and malignant tissues, they allow the collection of information on cancer presence, spread, and metabolism.

Recent scientific advances in nanotechnology, radiochemistry, reporter gene imaging, cancer stem cell imaging, and other fields now enable the development of novel imaging agents for:

·       Early detection and diagnosis of cancer

·       Differentiation of benign disease from malignancy

·       Stratification of patients for the purpose of selecting a cancer therapy

·       Surgical planning

·       Evaluation of tumor response to chemotherapy and radiation therapy

·       Detection of cancer recurrence

However, despite significant preclinical scientific progress, very few cancer imaging agents are actually available in the clinic. Therefore, this SBIR contract topic seeks to stimulate the commercialization of novel imaging agents, including: nanotechnology-based imaging agents, radiopharmaceuticals for positron emission tomography (PET) and single photon emission computed tomography (SPECT), targeted contrast agents for X-ray, computed tomography (CT), and magnetic resonance imaging (MRI), optical contrast agents, and reporter gene imaging technologies.

One specific area of interest under this topic is the development of single-domain antibody fragments used to target radionuclides for imaging and targeted radiotherapy of cancer. Single-domain antibody fragments comprise the single variable region of naturally-occurring antibodies that lack a light chain or engineered antibody fragments. This type of small protein or peptide has advantages over conventional antibodies and antibody fragments in terms of favorable and tunable clearance kinetics, ability to recognize hidden or uncommon epitopes, agent format flexibility, and ease of manufacture. Therefore, developing an imaging technology for early diagnosis of cancer at the molecular level based on single domain antibody fragments will be encouraged.

Project goals:

The short-term goal of this SBIR contract topic is to support research and development activity at small businesses that are developing cancer imaging agents. The imaging agent should be novel and, when appropriate, have high affinity and specificity against tumor targets. It should also display fast in vivo clearance, rapid tumor accumulation, sufficient in vivo stability and good biovailability, and low immunogenicity and toxicity. The work scope may include animal testing, formulation, GMP production, pharmacokinetic studies, pharmacodynamic studies, and toxicological studies. These data will support the rationale for continued development of the experimental medical imaging agent to the point of filing an Investigational New Drug application (IND).

The long-term goal of this contract topic is to enable small businesses to bring novel classes of fully developed cancer imaging agents to the clinic and the market. Therefore, businesses are encouraged to submit applications for development of lead compounds representing novel technology platforms.

Phase I Activities and Expected Deliverables:

Phase I activities should generate scientific data confirming the clinical potential of the proposed contrast agent. Some of the expected activities are:

·       Preparation ofan imaging agent.

·       Demonstration of capabilitiesenabled by the imaging agent with a high signal-to-noise ratio.

·       Quantification of the imagingsignals to determine the agent affinity and specificity.

·       Proof of concept pre-clinicalstudies.

·       Preliminary toxicologicalstudies.

·       Preparation of a development plan that describes in detail the experiments necessary to file an IND or an exploratoryIND.

·       Presentationof the Phase I results and the development plan to NCI staff.

The Phase I research plan must contain specific, quantifiable, and testable feasibility milestones.

Phase II Activities and Expected Deliverables:

Phase II should follow the development plan laid out in the Phase I, and should further support commercialization of proposed cancer imaging agents. Some of the expected activities are:

·       Completionof all pre-clinical experiments according to the development plan.

·       Demonstration of fast in vivo clearance, rapid tumor accumulation, sufficient in vivo stability, good bioavailability, and low immunogenicity/toxicity.

·       Demonstrationof high reproducibility and accuracy of the imaging technology in several animal models.

·       When appropriate, demonstration of similar or higher specificity and sensitivity of the technology when compared to other imaging technologies.

·       When appropriate, demonstration of capabilities to monitor efficacy of drugs in tumor cell lines and/or animals.

·       Productionof sufficient amount of clinical grade material suitable for an early clinical trial.

·       If warranted, filing of an IND or an exploratory IND for the candidate imaging agent.

·       Completionof a small-scale clinical study.

The Phase II research plan must contain specific, quantifiable, and testable feasibility milestones.

Current dietary assessment methods and systems largely depend on time and resource intensive self-report and/or recall methods. Accuracy of the assessment is often compromised when diet is assessed via self-report because of the cognitive challenges in recalling or reporting quantities, types, and preparation of foods eaten. Dietary assessment methods that do not rely solely on self-report and recall could enhance the accuracy and efficiency of dietary intake data collection and contribute to improved understanding of the diet-disease relationship. Technological and analytic advances over the past decade have led to more objective methods to assess dietary intake. Leading examples include sophisticated dietary image or short video capture devices, that may be housed on a mobile phone platform and paired with speech recognition, text interface, and/or geospatial location. With the advent of electronic medical records and the focus on the epidemic of obesity and related co-morbidities, clinicians, researchers, and practitioners are increasingly interested in using objective measures to monitor patient/participant behavior as a tool for chronic disease prevention or management and health research.

The development of an easily deployable architecture for image-based dietary data transfer, storage, analysis, and reporting will support the potential to increase understanding of the relationship between diet and cancer risk. However, software systems necessary to manage and analyze the rich media collected by mobile sensors are currently limited. The complexity of data management and analysis needed to provide image-based measures of dietary intake presents a significant barrier to the integration of these measures into clinical practice and trials, epidemiological research, and behavioral monitoring applications. To overcome current barriers and facilitate integration of image-based dietary measures into applications including electronic medical records and other health information systems, contracts shall stimulate development of an easily deployable architecture for data collection, transfer, storage, analysis, and reporting of dietary intake.

Project objectivesinclude:

1)       Development of a mobile application to facilitate and control the collection and transfer of dietary images or video, and any associated information such as annotations, probes, or geospatial location.

2)       Development of a standardized dietary rich media database architecture and procedures to import and store data transferred from the mobile application.

3)       Development of transparent and modifiable analytic tools that can incorporate existing and evolving methods to generate individual and group level dietaryintake measures from dietary images and associated data.

4)       Development of reporting systems to communicate outputs to patients/subjects, electronic medical records, health surveillance systems, or researchers.

Project Goals:

This topic addresses the need to develop high throughput, efficient methods to standardize collection, processing, and reporting of image-based dietary intake measures, for use in clinical and research settings, and for case management in prevention or treatment of chronic disease. This topic’s goal is to encourage development of mobile applications to facilitate and control the collection and transfer of dietary rich media files; and paired systems for data importation, storage, analyses, and output reporting of image-based dietary intake measures. Required data elements include dietary images or short video capture of consumed foods. Additional elements may include (but are not limited to) speech recording and recognition, text interface, and/or geospatial location. The NIH Genes, Environment, and Health Initiative (GEI) Exposure Biology Program has supported development of technology and analytic methods for image-based dietary assessment with relevance to the current topic.

An essential task for each proposal is the application or development of transparent and expandable analytic tools to generate summary individual level dietary measures from collected dietary rich media files. Data processing applications and analytic tools may be drawn from established or emerging methods for dietary image analysis research and practice. An expandable set of analytic tools for processing image and supplemental dietary input data shall be developed, including automated food item identification, quantity estimation, and consumed volume reconstruction based on pre and post-meal images/video. Data processing and analytic tools must provide linkages to established nutrient databases including the USDA Food and Nutrient Database for Dietary Studies (FNDDS) and the USDA MyPyramid Equivalents Database (MPED). Capacity to incorporate or expand to handle additional data is also encouraged, such as Global Positioning System (GPS) location or linkage to the Gladson Nutrition Database which includes Universal Product Code (UPC) data. Data linkages are required within the Dietary Intake Summary Database to identify individual level data characteristics based minimally on eating occasion or meal, day, and week.

Proposals must demonstrate implementation or development of data standards and capacity for sharing dietary summary measures via output reporting systems. Recommended short term targets for dietary outputs include ability to providereports to patients/participants, health systems, and researchers; with longer term targets to provide reports directly to electronic medical records and public health surveillance systems. Recommended reports are consistent with current health outcomes policy priorities and objectives in the Meaningful Use Matrix for electronic health records established by the Health Information Technology Policy Committee (see http://healthit.hhs.gov/portal/server.pt).

Potential steps within a developed systems data cycleare described below:

1)       A front end mobile application to facilitate and control dietary rich media data collection and transfers is deployed to a user’s smartphone.

2)       Usingthe front end mobile application, a user collects dietary image or short video files and system specific annotation options (such as speech recognition, text interface, or probing options) and/or geospatial location.

3)       Thefront end mobile application wirelessly transfers the collected data to the backend system for data management and processing.

4)       Using automated procedures, the transferred data is screened and imported into the structured Dietary Rich Media Database.

5)       Automated analytic tools are used to process images and supplemental data for food item identification, quantityestimation, and consumed volume reconstruction based on pre and post-meal images/video.

6)       Analytic tools link to established nutrient databases including FNDDS and MPED for nutrient intake and equivalentsestimation.

7)       Food and nutrient intake summary measures are stored within a Dietary Intake Summary Database with linkagesallowing individual or group outputs based on eating occasion or meal, day, week, and/or other periods of assessment.

8)       Reporting systems provide outputs directly to information users, such as the patient, research study site, or the patient’selectronic medical records for review and follow-up by health care team members.

Phase I Activitiesand Expected Deliverables:

·       Establish a project team including expertise in dietary assessment and food and nutrition science, image-based technologies for dietary assessment, advanced image data/signals processing methods, and database and computational systems that will effectively address all objectives of the current topic.

·       Providea report including detailed description and/or technical documentation of the proposed:

o   Database structure for the Dietary Rich Media Database

o   Data standards for collection, transfer, importation, and storage of image/video and annotation data

o   Expected sensor(s), mobile platform(s), mobile device(s), compatibility matrix for the front end mobileapplication to be developed

o   Datalinkages to identify individual level data characteristics based minimally on eating occasion or meal, day, and week

·       Developa functional prototype system that includes

o   A front end mobile application to facilitate and control the collection and transfer of dietary images or video, and any associated information used within the system

o   Automated data screening and importation protocols for files transferred from the mobile application to a structured Dietary Rich Media Database

o   Softwaresystems user-interface (web- or computer-based)

·       Providea report detailing planned analytic tools and resulting system capabilities for dietary intake summary data outputs. The analytic tools plan shall include justification for image processing algorithm source(s) selected or to be developed.

·       Provide a report detailing output reporting systems feasibility, proposed timelines, data standards, and communicationarchitecture for reporting dietary intake summary outputs to patients/subjects, electronic medical records, health surveillance systems, and researchers.

·       Finalizedatabase formats, repository structure, and data collection, transfer, and importation methods for targeted data inputs.

·       Includefunds in budget to present phase I findings and demonstrate the final prototype to an NCI evaluation panel.

Phase II Activitiesand ExpectedDeliverables:

·       Beta test and finalize front end mobile applications listed in phase 1.

·       Beta test and finalize automated file transfer, screening, and database importation protocols and systems.

·       Develop, beta test, and finalize analytic tools listed in phase 1.

·       Develop, beta test, and finalize applicable user interface systems.

·       Develop and beta test output reporting systems capabilities for multiple system output targets listed above.

·       Demonstrate system compatibility with sensor(s), mobile platform(s), and mobile device(s), included in the phase 1 compatibility matrix.

·       Develop systems documentation where applicable.

·       In the first year of the contract, provide the program and contract officers with a letter(s) of commercial interest.

·       In the second year of the contract, provide the program and contract officers with a letter(s) of commercial commitment.

·       Usability testing for both front end and back end aspects of the user-interface.

Cancer is recognized as a multistep process involving multiple genomic and epigenomic alterations that occur in multiple phases. The complexity of cancer requires multivariate assays for accurate diagnosis, prognosis and treatment monitoring. Recently, two multivariate gene-expression assays, Oncotype DX and MammaPrint, have been developed for determining whether chemotherapy is necessary for breast cancer. The Oncotype DX analyzes the expression of a 21-gene signature by TaqMan RT-PCR. The MammaPrint microarray which measures the expression of 70 breast cancer genes as a signature, provides information about the likelihood of tumor recurrence and guides treatment.

Given the multivariate and heterogeneous nature of the disease, it is likely that the early detection and diagnosis of cancer will be based on multiple analytes. However, the currently available clinical multi-analyte technology platforms have many limitations, including the requirement of multiple biopsies and special specimen collection/storage process. Additionally, their processes are often slow, complex, labor intensive and with sup-optimal sensitivity. These factors contribute to the added cost which also limits their broad applicability. For example the current list price of both Oncotype DX and MammaPrint are over $4000 per sample.

While the various NIH and other Government (DOD, DARPA, NSF, NASA, USDA etc) programs are developing new cutting edge technologies, their focuses are not on commercialization, and these novel technologies have not penetrated into clinical use. This contract topic seeks to promote the development of such innovations in early detection and diagnostic technology to facilitate the commercialization of low cost, efficient multi-analyte technologies with optimal sensitivity for cancer early detection, diagnosis and prognosis. In particular, this topic requests the development of technologies that can obtain multi-analyte molecular information from small volume clinical specimens (e.g. core biopsy, fine needle aspiration, circulating tumor cells or FFPE sections). In addition, this contract topic encourages proposals based on improving both early detection and diagnosis of cancer from easily accessible samples (e.g. blood, sputum, urine, fecal) with low abundant cancer markers.

Project Goals:

The short-term goal for the project is to develop working prototypes of low cost devices or methodologies for multi-analyte analysis of small samples or easily accessible samples with low abundant cancer biomarkers. Long-term goals are to improve cancer early detection, diagnosis, prognosis and treatment monitoring by developing low cost, more efficient, and more sensitive devices or methodologies for multi-analyte detection and analysis. Additionally, this topic requests the development of technologies that can be used with small volume, small numbers of cells or low cancer biomarker abundant clinical specimens obtained through regular biopsy procedures (e.g. core biopsy, FNA), surgery (e.g. FFER sections) or minimally invasive methods (e.g. blood, sputum, urine, and fecal). The technology should be innovative and make use of recent advances in areas such as microfluidics, nanotechnology, multichannel imaging, and transducer technologies for biosensors including optical, electrochemical, piezoelectric, Field Effect Transistor, cantilevers or any other rapid multi-analytes transducers. These devices and methodologies should be more cost efficient than current ones (>5x cost reduction), have significantly improved sensitivity/specificity (>10x) and can be used with samples obtained from single core biopsy or FNA. Acceptable devices and methodologies should be able to analyze at least 30 markers (DNA, RNA, RNAi, or proteins) simultaneously within four hours. If the innovation includes an integrated device, the cost of the market ready device should be less than $15,000. Ideally, the input for the device should be core biopsy, FNA or any small clinical biopsy specimen and the output should be the profile of the markers. This solicitation also encourages developing non-invasive biomarker based technologies and available multi-analyte technologies and assays for cancer early detection.

Accepted devices or methodologies include, but are not limited to:

·       Rapid sample preparation and multi-analyte concentration technologiesfor high quality DNA/RNA RNAi/protein/cell

·       Multi-analyte amplification technologies for DNA,RNA, ncRNAs, RNAi, proteins, and glycoproteins

·       Low-frequency mutation analysis (e.g. for multiple relevant genetic markers/mutations)

·       Rapid DNA sequencing (e.g. for multiple relevant genetic markers/mutations)

·       Advanced PCR techniques

·       New protein or DNA/RNA/ RNAi labeling and label free technologies. Preference will be given to label free technologies

·       Point of Care DNA, RNA or antibody microarrays

·       Automated integrated system

Phase I Activities and Expected Deliverables:

·       Development of the essential components of the proposed technology.

·       Demonstration of the feasibility of the technological innovation (e.g. spiking relevant body fluids with cancer cells or using FFPE). The offer should include benchmarking studies against current technologies. When possible, material that requires IRB approval to acquire or study should not be used for phase I.

·       Characterization of the variation, reproducibility and accuracy of the method.

·       Provide NCI with a detailed report of the number of cells and sample size needed, potential biomarker panels for the technology, estimations of sensitivity, selectivity, the cost of producing the proposed devices and/or reagents, including an analysis/breakdown of vendors and/or sources of raw materials.

Phase II ActivitiesandExpected Deliverables:

·       Develop a prototype of the device or analytical tool incorporating the technology demonstrated in Phase I including automation, software and data analysis.

·       Test the device with clinically relevant cancer biomarkers.

·       Test with a sufficient number of patient samples in several laboratories to demonstrate concordance, clinical utility and advantages, with an appropriate consideration of statistical significance.

The capacity to present defined, pre-selected samples of archival tissue for immunohistochemical and in situ molecular analysis has revolutionized the development and validation of tissue-based biomarkers in research and clinicalapplication. In the clinical setting, most new diagnoses of cancer use immunohistochemical assays of tissue samples to support the diagnoses, and these immunohistochemical assays must be carefully calibrated and validated. Tissue microarrays are the means for validating the accuracy of these tissue diagnostic assays. Tissue microarrays can present hundreds of tiny discs (range 0.6 to 3.0 mm) of human or animal tissue specimens, arranged in a grid on a single microscope slide. Currently available arraying tools are capable of fabricating hundreds to thousands of copies of one such slide. Arraying tools can be quite expensive (especially the automated tools) , complex, and require special training to operate and maintain quality. These tools are therefore often beyond the resources of many laboratories that either have to settle for lower quality slides produced without instrumentation, or purchase slides from manufacturers or specialty labs. Thus, a need exists for a simple and inexpensive instrument for fabricating tissue microarrays in clinical settings and research laboratories.

In the research setting, a typical application of tissue microarrays is the analysis of several hundred breast tumor tissue samples from patients at different stages of disease development (normal tissue, in situ cancer, invasive cancer, metastases) to identify the specific step at which biologic alterations take place, as well as the frequency of these alterations. In another example, tissue microarrays can be constructed from tissue materials in a retrospective study design, where one can immediately correlate the expression of a molecular marker with poor prognosis or response to therapy. Furthermore, coupling with automated imaging platforms is possible, and multiple different tumor types along with normal tissues can be screened simultaneously.

Researchers at NCI have invented an instrument for manual construction of tissue microarrays that is projected to be more accurate and less expensive than currently available. The invention requires further proof of concept to establish reliability, accuracy, and precision, and development of a fully functional prototype capable of being manufactured in quantity.

This inventionis the subject of issued U.S. Patent Number 7,854,899 and HHS Reference Number E-098-2004/0.

Project Goals:

The preliminary goal of this project is to develop a functional prototype capable of generating tissue microarrays using the described methods. The final product will be a modular system that will enable clinical and research laboratoriesto construct tissue microarrays on a routine basis. The long term goal of this project is to bring to market this simplified, low-cost instrument for tissue microarray construction to meet the needs and applications of researchers and clinicians as described below.

This is an NIH TT (Technology Transfer) contract topic from the NCI. This is a new program whereby inventions from the NCI Intramural Research Program (Center for Cancer Research, CCR) are licensed to qualified small businesses with the intent that those businesses develop these inventions into commercial products that benefit the public. The contractor funded under this contract topic shall work closely with the NCI CCR inventor of this technology, who will provide non-human tissue samples, as well as other reagents as needed. The inventor will provide assistance in a collaborative manner with reagents and discussions during the entire award period. Between the time this contract topic is published and the time an offeror submits a contract proposal for this topic, no contact will be allowed between the offeror and the NCI CCR inventor. However, a pre-submission public briefing and/or webinar will be given by NCI staff to explain in greater detail the technical and licensing aspects of this program (for further information, see http://sbir.cancer.gov/news/upcoming/). In addition, a list of relevant technical, invention, and licensing-related questions and answers (including those from the public briefing) will be posted, maintained, and updated online (http://sbir.cancer.gov/news/upcoming/) during this time period.

The awarded contractor will automatically be granted a royalty-free, non-exclusive license to use NIH-owned and patented background inventions only within the scope and term of the award. However, an SBIR offeror or SBIR contractor must negotiate an exclusive or non-exclusive commercialization license to make, use, and sell products or services incorporating the NIH background invention. An SBIR contract proposal will be accepted as an application for a commercialization license to such background inventions. Under the NCI NIH TT program, the SBIR contract award process will be conducted in parallel with, but distinct from, the review of any applications for a commercialization license.

Model licenseagreements are available at http://www.ott.nih.gov/forms_model_agreements/forms_model_agreements.aspx#LAP. Certain terms of the model license agreement are subject to negotiation. Please contact NIH Licensing and Patenting Manager (Cristina Thalhammer-Reyero, 301-435-4507, thalhamc@mail.nih.gov) with further questions.

Licensingprocedures will comply with Federal patent licensing regulations as provided in 37 CFR part 404. A further description of the NIH licensing process is available at http://www.ott.nih.gov/licensing_royalties/intra_techlic.aspx. NIH will notify an SBIR offeror or SBIR contractor who has submitted an application for an exclusive commercialization license if another application for an exclusive license to the background invention is received at any time before such a license is granted.

Any invention developed by the contractor during the course of the NIH TT contract period of performance will be owned by thecontractor subject to the terms of Section 8.5.

Phase I Activitiesand ExpectedDeliverables:

·       Develop an instrument as instructed in U.S. Patent 7,854,899 with

o   Capacity of 100 samples on a single microscope slide for immunohistochemical analysis;

o   Controls for immunohistochemistry, as well as clinical assay validation;

o   Capable of fabricating replicate arrays.

·       Develop improved prototype with component parts, including:

o   Optimized needle(s) material and design;

o   Optimized templates design and features;

o   A donor block holder;

o   A recipient block holder/alignment device;

o   A recipient block-recipient-holes template;

o   A recipient block core-placement alignment template;

o   A needle holder/plunger device.

·       Process and cost estimates for manufacture of the minimum number of tissue arrayers to accommodate 10% of current market.

·       Provide NCI with all data resulting from Phase I Activities and Deliverables.

Phase II Activitiesand Expected Deliverables:

A Phase II proposal will typically only be invited by NCI if the Phase I contractor has been granted a commercializationlicense via the process described above.

·       Build prototypes of the tissue arrayer that incorporates the following:

o   A multi-recipient block tissue arrayer appropriate for research use.

o   Capable of daily run, large core, low multiplicity immunohistochemical controls.

o   Capable of immunohistochemical assay validation for use with samples of moderate core size and scalable multiplicity.

o   Capable of controlling the temperature of the donor block holder, the recipient block holder, and the needle.

o   Capable of fabricating arrays in substrates other than paraffin blocks including, but not limited to, other solid/semi-solid embedding substrates and frozen materials.

·       Design, optimize and evaluate the Phase I prototype as well as alternative Phase II prototypes by using the devices to construct tissue microarrays using tissue samples and then using the resulting tissue microarrays for:

o   Immunohistochemical controls

o   Validation of immunohistochemical tests

o   Immunohistochemistry and/or in situ assays in a research setting.

·       Demonstrate that the Phase II prototype can produce tissue microarrays of equal quality to those constructed with current technology, according to the following quantitative metrics:

o   Presence of 95% of cores of tissue in array design (in first sections)

o   Alignment of cores, with less than 10% displacement

o   Less than 5% of cores placed off of perpendicular to array face

o   Generation of an equal number of TMA sections compared to current technology (within 5%).

o   95% of cores without carry-over tissue from previously placed tissue cores.

·       Provide data on the use of the tissue microarray by research facility staff for routine analytic protocols and of staff training in using the prototypes, as compared to other comparably priced arrayers.

·       Develop a robust and scalable process for the manufacture of the tissue arrayer produced in Phase I.

·       Provide NCI with all data resulting from Phase II Activities and Deliverables.

The adoptive transfer of autologous tumor reactive T lymphocytes (T cells) can mediate significant tumor regression and long term cures in patients with refractory metastatic cancer. Despite these important clinical findings, adoptive cell transfer has not become widely available for patient treatment. Obtaining tumor infiltrating lymphocytes (TIL), T cells associated with a tumor that can exhibit high tumor reactivity, usually requires invasive surgery, which can lead to post-operative complications and is not always possible for all patients depending upon the location of their tumors. A significant obstacle in extending this promising therapy to a broader range of cancer patients has been the availability of highly efficient in vitro methods to rapidly isolate and expand tumor reactive T cells from peripheral blood for therapeutic use. Due to the low frequency of these T cells in the peripheral blood of cancer patients, isolation of these cells has traditionally been a difficult and laborious process requiring prolonged culture times and large amounts of reagents and equipment. Furthermore, the T cells typically generated during this protracted in vitro process develop unfavorable traits making them unsuitable for cancer therapy.

To overcome this significant challenge, intramural NIH investigators have invented a novel high throughput in vitro platform using quantitative RT-PCR (qPCR) as a functional screen to rapidly detect and isolate a variety of low frequency tumor reactive T cell clones from the peripheral blood of cancer patients (U.S. Patent Application No. 61/027,623). This novel technology has allowed the investigators to isolate and expand unique human T cells under GMP conditions that otherwise would not have been feasible. The utility of these inventions has been demonstrated by their application in isolating rare T cells and expanding them for human cancer therapy in an NCI sponsored clinical trial (NCI 08-C-0104).

This invention is the subject of U.S. Patent Application Number 12/866,919 and foreign counterparts in Europe and Australia(HHS Reference Number E-003-2008/0).

ProjectGoals:

The ultimate goal of this solicitation is to further refine and develop this novel T cell isolation platform into a standardizedmanufacturing operating procedure that could be commercialized for public and private use. The development of this technology would help overcome the fundamental obstacle of isolating highly tumor reactive T cells that circulate at low frequencies in the human body, which currently has prohibited the widespread use of adoptive T cell therapies. A current approach to obtain these low frequency tumor reactive T cells, such as TIL, from cancer patients is to use invasive surgical procedures to resect tumor and isolate TIL from the resected tumor. However, some tumors cannot be resected without risking patient mortality. The development of this current technology would provide patients with unresectable tumors another option for isolation of therapeutic T cells. If successful, this technology could potentially become the standard for tumor reactive T cell isolation and eliminate the need for the invasive surgical approach. The second long term goal of this solicitation is the development of novel applications for this T cell isolation platform, such as extending its applicability to other cancers and other disease indications. The awardee may have an opportunity to engage in collaborative research with NCI’s researchers and benefit from current expertise in the field for preclinical development and the clinical application of the technology.

This is an NIH TT (Technology Transfer) contract Topic from the NCI. This is a new program whereby inventions from the NCI Intramural Research Program (Center for Cancer Research, CCR) are licensed to qualified small businesses with the intent that those businesses develop these inventions into commercial products that benefit the public. The contractor funded under this contract Topic shall work closely with the NCI CCR inventor of this technology, who will provide patient samples, necessary assay equipment, as well as other reagents as needed. The inventor will provide assistance in a collaborative manner with reagents and discussions during the entire award period. Between the time this contract topic is published and the time an offeror submits a contract proposal for this Topic, no contact will be allowed between the offeror and the NCI CCR inventor. However, a pre-submission public briefing and/or webinar will be given by NCI staff to explain in greater detail the technical and licensing aspects of this program (for further information, see http://sbir.cancer.gov/news/upcoming/). In addition, a list of relevant technical, invention, and licensing-related questions and answers (including those from the public briefing) will be posted, maintained, and updated online (http://sbir.cancer.gov/news/upcoming/) during this time period.

The awarded contractor will automatically be granted a royalty-free, non-exclusive license to use NIH-owned and patented background inventions only within the scope and term of the award. However, an SBIR offeror or SBIR contractor mustnegotiate an exclusive or non-exclusive commercialization license to make, use, and sell products or services incorporating the NIH background invention. An SBIR contract proposal will be accepted as an application for a commercialization license to such background inventions. Under the NCI NIH TT program, the SBIR contract award process will be conducted in parallel with, but distinct from, the review of any applications for a commercialization license.

Model license agreements are available at http://www.ott.nih.gov/forms_model_agreements/forms_model_agreements.aspx#LAP. Certain terms of the model license agreement are subject to negotiation. Please contact the designated NIH Licensing and Patenting Manager(Samuel Bish, Ph.D., 301-435-5282, bishse@mail.nih.gov) with further questions.

Licensingprocedures will comply with Federal patent licensing regulations as provided in 37 CFR part 404. A further description of the NIH licensing process is available at http://www.ott.nih.gov/licensing_royalties/intra_techlic.aspx. NIH will notify an SBIR offeror or SBIR contractor who has submitted an application for an exclusive commercialization license if another application for an exclusive license to the background invention is received at any time before such a license is granted.

Any invention developed by the contractor during the course of the NIH TT contract period of performance will be ownedby the contractor subject to the terms of Section 8.5.

PhaseI Activitiesand Expected Deliverables:

Platform Development:

·       Develop protocol for T cell stimulation and growth in 384 well plate format to increase current throughput.

·       Develop protocol for RNA isolation in 384 well format to increase current throughput.

·       Develop 384 well multiplex qPCR assay for cytokine profiling.

·       Apply automated liquid handling technology to facilitate high throughput screening.

·       Apply automated liquid handling technology to facilitate T cell cloning.

Phase II Activities and Expected Deliverables:

A PhaseII proposal will typically/generally only be invited by NCI if the Phase I contractor has been granted a commercialization license via the process described above.

Development of novel application:

·       Epitope Discovery: Develop a novel high-throughput methodology to rapidly screen a peptide library of predicted peptides from putative antigen targets by analyzing their ability to stimulate human leukocyte antigen (HLA) matched human peripheral blood lymphocytes (PBLs).

·       Utilize current platform to identify functional gene expression signatures for unique T cell populations.

·       Isolation of novel T cell populations for human cancer therapy clinical trials.

NCI is committed to developing clinically useful biomarker tests that identify critical molecular targets within a patient's tumor, which can provide drug sensitivity, resistance, and real-time response information. For this SBIR topic, NCI requests that qualified small businesses submit proposals to aid the development of robust, quantitative pharmacodynamic (PD) immunoassays. Specifically, this topic solicits proposals to develop methods for the generation of stable, site-directed, high-content (50-80%) post-translationally modified (e.g., phosphorylated) protein calibrators AND associated processes for bench-top purification, characterization and qualification of these protein calibrators

Approximately 30% of proteins in eukaryotic cells are subject to phosphorylation. This crucial post-translational modification of proteins regulates numerous normal cellular events including the cell cycle, differentiation, metabolism, and neuronal communication. Likewise, dysregulated phosphorylation has been implicated in the etiology of many diseases. Thus, pharmacodynamic (PD) assays that directly detect and quantify phosphorylated proteins serve as a means to assess the type and magnitude of the cellular response to an external stimulus (i.e. cancer drugs). Given the important role kinases play, it is critical for researchers to have quality tools: (1) to generate stable post-translationally modified protein calibrators, particularly phospho-proteins; (2) to accurately identify the post-translationally modified sites; and (3) to quantify the level of site-specifically modified protein residues. Such reference standards are critically needed to serve as calibrators for absolute quantitation in PD assays. Moreover, the NCI anticipates that a subset of the PD assays that use these calibrators may ultimately be repurposed as companion diagnostic assays for approved drugs.

Producing post-translationally modified proteins (e.g., phospho-proteins) is currently imprecise involving chemical, enzymatic, and recombinant techniques. For example, biological systems provide poor control over site-directed phosphorylation and the percentage of phosphorylation at each site. A detailed characterization of the sites of post-translational modification is also difficult, with quantitation or semi-quantitation of modified residues now being carried out by mass spectrometry, fluorescence immunoassays, Microscale Thermophoresis (MST), FRET, Time-Resolved Fluorescence (TRF), fluorescence polarization, and ELISA. The development of technologies for producing high quality, high content, and analytically verified post-translationally modified proteins is becoming increasingly important for the systematic analysis of complex cell signaling networks that drive normal and abnormal cellular function. Thus, there is a great need to develop new approaches for quantitative generation and characterization of post-translationally modified proteins, which could encompass one or more of the methods above and be designed to be time-, labor-, and money-saving.

A primary roadblock in the development of robust, quantitative assays for the detection of post-translationally modified proteins is the lack of well-defined turn-key processes for the production and characterization of purified proteins that are quantitatively modified at particular amino acid residues but not others. (Such reference standards are critically needed to serve as calibrators.) Improving the quality of clinical grade assay development for post-translationally modified proteins will require the development of methods/systems that allow the reproducible generation of stable protein calibrators by directed and quantitative modification of certain residues (50-80% of the specified site), but not others (90-100% of the remaining sites should remain unmodified). Such methods and systems should be capable of evaluating the effectiveness of the post translational modification process, including an assessment of the heterogeneity of the modifications generated. The method/system should also be capable of assessing the effectiveness of the purification method(s), enabling both the detection of impurities and lot-to-lot comparisons.

The focus of this topic is to use innovative, state-of-the-art technologies to develop turn-key systems/processes that can provide assay-specific, stable post translationally modified proteins with reasonable throughput and the analytic verificationof the particular modified residue(s) and level of modification. The desired outputs include reproducible production of post translationally modified protein calibrators, identification of the modified residue(s), 50-80% modification of the specified sites, purity, yields, and possibly other parameters (e.g., percent native vs. denatured protein). Easy-to-use, on-demand, bench top generation and characterization processes/systems will be applicable to a broad range of medical and biomedical applications in both academics and industry.

Thus, the overarching goal of this topic is to extend capabilities for the NCI and the broader cancer community to generate robust, quantitative protein-based assays to enable more efficacious, targeted therapeutic treatment of cancer patients.

Proposals submitted under this topic should include a detailed strategy/plan to develop the appropriate methodology, reagents, and instrumentation/processes to produce stable, high-content, site-specific, post-translationally-modified (e.g., phosphorylated) protein calibrators. Offerors submitting proposals under this topic are encouraged toconsider focusing on the production of calibrators from the list of molecular targets below, which are of particular interest to the NCI. However,proposals may focus on the development of any protein target and/or cancer-relevant post-translational modification of clinical relevance to cancer.

Proteins/targets of particular interest to the NCI:

Receptor Tyrosine Kinases
MET
RON
EGFR
ALK
IGF1R

Non-Receptor Tyrosine Kinases
SRC
FAK
JAK
ABL
CSK

Project goals:

The goal of the NCI SBIR program is to fund small businesses to develop commercially viable products that advance the research and development needs of the Institute and the broader cancer community. It is expected that companies submitting proposals under this topic will execute and extend their work to develop marketable instrumentation that enhances the qualification of critical protein reagents for use in PD and other types of diagnostic assays for cancer patients. The NCI Strategic Plan identifies validating molecular targets for cancer prognosis, metastasis, treatment response, and progression as a strategic priority (Strategy 4.2). Part of this strategy includes creating a library of validated molecular target assays to advance broad development of targeted anti-tumor agents.Assay development encompasses the provision of qualified critical protein reagents as capture and detection agents, calibrators, or controls. One reason for the slow adoption of PD and patient characterization assays is inconsistency in assay performance between sites, and a primary cause of this performance variability is the lack of qualified critical reagents. Market analysis indicates that qualified critical reagents are essential for rapid clinical adoption of new assays, especially the initial “home-brew” assays developed in CLIA-certified laboratories and in small biotechnology companies without the financial means to contract out reagent qualification. Development of technologies to include methodologies and/or prototype instrument systems for rapid, turn-key, bench-top generation of qualified post-translationally modified (e.g., phospho-protein) calibrators will be a valuable step toward the eventual commercialization of diagnostic assays that target post-translationally modified proteins associated with disease or drug action.

Phase I Activities and Expected Deliverables:

·       Methodology, reagents, and instrumentation (if applicable) to produce stable site-directed, high content (>50%) post-translationally modified (e.g., phospho-protein) calibrators or calibrators/controls

·       Develop and deliver method, reagents, and a prototype instrument system (if applicable) that allows identificationand quantification of site-specific protein modification

·       Performexperiments and provide data that demonstrate reproducibility, variability, and accuracy of the technologies in comparison to reference materials and gold standard techniques for at least 5 of the designated targets, to include at least one receptor tyrosine kinase

·       Deliverto NCI the generated calibrators and associated processes/technologies with applicable SOP(s) (Appendix 1) and Certificate of Performance(s) (Appendix 2)

·       Deliver software (macros) for capture of data readouts and calculation of the requested variables

·       Make available to NCI sufficient reagents and instrumentation to perform 10 test runs for independent validation

·       Provide technicalsupport and one on-site training session for NCI

Phase II Activities and Expected Deliverables:

·       Processes should be optimized to generate quantitative, site-specific post-translational modification with the highest level of modification feasible (>80% preferred), for all the designated protein residues of interest

·       Refine and develop validated, CLIA-quality protocols, reagents and instrumentation systems (if applicable) withQuality Control and calibration protocols and standards for all analytic parameters for all of designated protein targets described in Phase I

·       Perform full validation of the protocol and instrumentation prototypes with a statistically significant number of runs, and provide data that characterize reproducibility, variability, and accuracy of the refined technologies [three lots of calibrators for all designated protein targets must be evaluated; all generated calibrators and the Certificate of Performances and SOPs of CLIA quality for use of the technologies and performance of all analytic characterizations are to be delivered to NCI (Appendix 1- 2)]

·       Establish quality control measures and carryout critical reagent supply chain audits; evaluate the quality of supply chain for key reagents, materials, and instrumentation; provide data supporting consistent quality; and determine the accessibility to maintain supply chain

·       Provide the NCI with access to the refined instrument(s) and sufficient reagents for 10 test runs of each analytic parameterfor independent validation

·       Provide technicalsupport and one on-site training session for NCI

Provide the program and contract officers with a letter of commercial interest

The mission of the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP) is to maximize public health and safety nationally and internationally through the elimination, prevention, and control of disease, disability, and death caused by HIV/AIDS, Viral Hepatitis, other Sexually Transmitted Diseases, and Tuberculosis.

NCHHSTP Web site:  http://www.cdc.gov/nchhstp/

The field of HIV prevention has recently gained two new biomedical preventions: 1) a partially effective HIV vaccine, RV-144 delivered parenterally, and 2) partially effective pre-exposure prophylaxis (PrEP) in the form of a microbicide delivered as a vaginal gel, or as a daily, oral tablet. These preventions, while not yet approved for general use, are - either in the same form or in modified form - imminently scalable and likely to be implemented widely in upcoming years. CDC has been involved in evaluating and developing biomedical preventions such as these for many years, both in animal models and in humans. Historically, CDC has also provided guidance on implementation of vaccines, and through ACIP, will do so for HIV vaccines as they emerge.

It is likely that future HIV vaccine trials in humans will have to incorporate control arms with PrEP, be it by oral, vaginal or rectal delivery. The partial efficacy observed with a single intervention, whether it be a vaccine or PrEP, has escalated the need to assess if these two combined preventions will have additive, synergistic or possibly even negative/inhibitory effects. CDC researchers have used statistical models to explore these questions. However, animal models allow direct testing of the combined efficacy of partially effective prevention methods. CDC and the field of HIV prevention would gain immensely from such preclinical results. This could directly inform clinical trial designs, and also inform implementation of novel preventions.

Project Goal:  The goal of this project is to model, in non-human primates, combination preventions such as PrEP and candidate HIV vaccines, to determine if these combinations have neutral, additive, synergistic, inhibitory or other effects.

Vendors should have prior experience testing animal models of HIV, anti-retrovirals or microbicides for HIV prevention and HIV vaccines. Proposals should include studies of at least 2 preventions for HIV infection (such as PrEP and a candidate HIV vaccine) that are representative of products in the current pipeline for human use. Furthermore, proposals should include a timeline, and should incorporate statistical estimates or sample sizes for different study arms that will allow appropriately powered evaluation of additive, synergistic or other interactions. Proposals may be structured to test study arms sequentially. Experimental design should include ways to measure correlates of protection and mechanisms of interaction. Studies should be designed with the long-term goal of providing information that will guide either human clinical trials of combination prevention, implementation of combination preventions or both. 

The incidence of hepatitis A (HAV) is falling rapidly, but outbreaks of food-borne HAV outbreaks occur occasionally, and can involve large numbers of people. An estimated 50,000 Americans acquire new hepatitis B (HBV) infection annually. The health burden of persistent or chronic HBV infection is also heavy, with high mortalities due to cirrhosis or cancer. Adding to the burden of 1.2 million people in the USA estimated to be chronically infected with HBV is an estimated 40,000 foreign-born, chronically infected persons per year resulting from immigration. Chronic HBV causes liver cancer, and this cancer is a leading cause of death for certain population groups in the USA such as Asian-Americans. Hepatitis C (HCV) is the most common chronic blood borne infection in the United States, affecting 3.2 million of Americans. Since 2000, an estimated 85,000 new HCV infections occur every year and approximately 19,000 new infections occurred in 2006. However, 50% of HCV infected persons are unaware of their infection. Additionally, several studies have estimated that 30% of HIV-infected individuals are also infected by HCV and 60-90% of individuals infected with HIV by intra-venous drug use (IVDU) have HCV. The total estimate for co-infected individuals in the USA is 300,000. About a fifth of the American population is estimated to be exposed to hepatitis E (HEV), but the health impact of this exposure is unknown.

Hepatitis viruses are a diverse group of viruses with different major modes of transmission. Hepatitis A and hepatitis E viruses (HAV and HEV) may cause food-borne outbreaks. Hepatitis B and hepatitis C viruses (HBV and HCV) are blood-borne viruses. Although, infection with any of the hepatitis viruses has a similar clinical presentation, the degree of sequence heterogeneity of these viruses varies. Recent advances in laboratory technologies and computational biology have facilitated a comprehensive sequence analysis of the genomes of hepatitis viruses. This information allows for further refinement of molecular epidemiological approaches and provides opportunities to link molecular epidemiological data to demographic, clinical, laboratory and epidemiological data. In the course of engagement in clinical and surveillance studies and outbreak investigations, CDC generates, collects and analyzes such data. Because of the diversity in the type and sources of these data the CDC’s seeks a software application that will be able to integrate these disparate datasets and that will permit data mining and investigator-initiated analysis.

Project Goal:  The goal of this project is to develop data mining software that extracts, transforms, and loads structured data relating to infection with hepatitis viruses from diverse sources into a warehouse appropriate for mainframe, client/server, and PC platforms. This data will include but may not be limited to demographic, clinical, epidemiological, laboratory and phylogenetic information. The software will store and manage the data in a relational database system with a web-based interface to provide data access to the scientific community and analysis of relationships in the stored data using end-user defined queries to discover disease patterns and trends. The software will have hook interfaces which allow data to be exported to external programs for additional analysis, and capture those results into the database. The software will also export the outcomes of such analyses in publication ready formats.

Impact:  It is expected that the software will generate associations between epidemiological and laboratory data leading to the discovery of new disease patterns, epidemiological trends and proteomic associations. Such discoveries are expected to lead to new strategies for public health interventions, surveillance, prophylaxis and the development of antivirals and vaccines. This software tool will be applicable not only to hepatitis viruses but other pathogens in the areas of epidemiology, laboratory research and public health.

Adolescent births and sexually transmitted infections (STIs) remain serious public health issues in the U.S. Although the U.S. teen birth rate fell to an all-time low in 2009, it remains the highest among all developed countries. National data indicate that one in four adolescent females (14-19 years) has an STI. In 2007, 13% of high school students had been tested for HIV. Although adolescents have clear reproductive and sexual health care needs, it can be difficult to connect adolescents to sexual and reproductive health care that takes into account their unique needs. Confidentiality, transportation, hours of operation, and payment can all serve as barriers to referral to, and use of, appropriate youth reproductive and sexual health care. Schools can serve as an important source of referral to health care providers in the community, and evidence-based models such as that of Project Connect can help adolescents to access youth-friendly health care.

Project Goal:  The goal of the project is to develop a software package featuring a location-based application that can be used on a cell phone or tablet to provide the location of adolescent reproductive and sexual health care providers local to the user. In addition, the application should have a web-based portal and SMS functionality (i.e., short message service, texting). The application would provide the name, location, and hours of service of the health care provider; contact information; services provided; fee for service and reimbursement options; transportation options; and directions. Additionally, health care providers would be screened for the extent to which their services are adolescent-friendly. Additional functionality may include the possibility of anonymous reviews and ratings by adolescents on service providers. Feasibility studies for this application would be conducted in Detroit, Michigan, and Los Angeles, California. Detroit is the site of a current replication of Project Connect, and Los Angeles was the original study site. Vendors should have expertise in sexual health among adolescents, school health, and sexual risk reduction strategies. Further, successful vendors will have expertise in youth usage of social media.

Extensive collaboration is likely for this project. This application overlaps with the STD and HIV testing site locator Web site in that it provides a listing of health care providers and locations and may extend the functionality of this Web site. Further collaboration would be done with Project Connect investigators and youth health care providers within community, school, district, and health departments in Detroit and Los Angeles. This research would benefit on-going efforts to link youth to care nationally and facilitate use of the Project Connect model, as well as to more effectively link youth to care in the selected cities.

Impact:  This application would increase the effective referral to and use of reproductive and sexual health care resources for youth in metropolitan areas with high prevalence of HIV, STI, and pregnancy among adolescents. Broader use of a developed application would be used by youth, school health care providers, and community health care providers and would provide services that would prevent or provide care for HIV and STIs nationally.

The Office of Public Health Preparedness and Response (OPHPR)’s mission is to strengthen and support the nations' health security to save lives and protect against public health threats. OPHPR has primary oversight and responsibility for all programs that comprise CDC's public health preparedness and response portfolio. Through an all-hazards approach to preparedness-focusing on threats from natural, biological, chemical, nuclear, and radiological events-OPHPR helps the nation prepare for and respond to urgent threats to the public's health. PHPR carries out its mission by emphasizing accountability through performance, progress through public health science, and collaboration through partnerships.

CIO’s Web site link:  http://www.cdc.gov/phpr/about.htm

Motor vehicle injuries are a main cause of morbidity and mortality for first responders (police, fire, ambulance/EMT, and military), and delays in emergency response. Intersections are a frequent location for these incidents, with emergency vehicles approaching at a high rate of speed, often against traffic signals. Despite the use of sirens and flashing lights, other vehicles are not always aware that they are on a collision course with an emergency vehicle. Increasingly, many drivers may be distracted from the use of personal wireless electronic devices and are unaware of the sirens or flashing lights of first responders.

Project Goal:  The goal of this project is to develop technologies to interface with personal wireless systems. These technology interfaces would enable first responders and other emergency vehicles to send out wireless messages (i.e., alerts to cell phones, GPS devices, etc.), located in private motor vehicles in the immediate vicinity of the responder. In addition to a proximity alert, this technology could also send wireless signals to vehicle based GPS devices showing location and direction of movement of emergency vehicles in relation to the private vehicle’s GPS device.

Impact:  Private driver situational awareness is critical to avoid vehicle crashes and related injuries associated with emergency vehicles transiting to or from emergency incident locations. The widespread use of wireless devices by drivers of motor vehicles will continue to increase as new technologies are developed in this market sector. Technologies that alert drivers of the proximity of emergency vehicles will reduce both morbidity and mortality of first responders as well as the general public. This technology will also increase response time and may result in more lives saved.

The National Center for Research Resources (NCRR) provides laboratory scientists and clinical researchers with the tools and training they need to understand, detect, treat, and prevent a wide range of diseases. NCRR supports all aspects of clinical and translational research, connecting researchers, patients, and communities across the nation. This support enables discoveries made at a molecular and cellular level and through animal-based studies. These discoveries are translated to patient-oriented clinical research, with the ultimate aim of improved patient care. Through its programs, NCRR stimulates basic research to develop and provide access to state-of-the-art technologies and instruments for biomedical and clinical research; improves the public understanding of medical research; and provides information about healthy living. NCRR supports all aspects of clinical and translational research, connecting researchers, patients, and communities across the nation.

Non-mammalian models, such as zebrafish, have emerged as powerful model organisms due to the availability of a wide array of species-specific genetic techniques, along with its short development time, fecundity and small size. For zebrafish larvae, their small size and optical clarity allows the use of powerful optical techniques that enable precise cellular visualization within the living animal, attributes that increase the ease of screening and allow screening on a large scale. Given the large number of zebrafish mutant and transgenic lines expressing fluorescent proteins, they can be utilized for large-scale chemical and therapeutic screens to identify lead compounds for drug discovery. Importantly, since the approach does not depend upon the prior identification of a target, it can be utilized to reveal novel insights and to dissect complex molecular pathways.

Despite the potential of the zebrafish for small molecule screens, very few have been reported and involve limited numbers of compounds. A key challenge has been the automated assessment of phenotypes because there are few image analysis methods capable of capturing the complexity of the whole organism. Additionally, throughput for zebrafish and other non-mammalian screens, for the most part, does not nearly approach that of high throughput screening (HTS) in cell culture systems. A principal hurdle to allowing more scientists to perform HTS using zebrafish is centered on the development of technology for automated image acquisition and data analysis. Although fluorescent microscopes with automated stages that allow examination of zebrafish embryos in microtiter plates have been developed, there are still many obstacles that impede optical access (e.g., pigmentation and the highly autofluorescent yolk sac), high-resolution image capture and analysis.

This contract topic seeks to stimulate research and development of a HTS automated system for imaging and analyzing zebrafish embryos and larvae that will be available commercially as a standardized, streamlined process, involving 2 or 3 pieces of equipment, requiring minimal laboratory space and that could be maintained and operated efficiently by a single person. Ideally, most of the process would be automated and all of the components listed below should be integrated into a single unified platform. Short of complete integration of all aspects, priority will be given to integration for each of two sub-groupings:

1.       Microfluidic platform for automated sorting of zebrafish embryos and young larvae (e.g., mutant vs. wildtype) that will load directly into the wells of a screening microplate, pipette test substances into embryo-containing wells at appropriate final concentrations, allow for incubation ideally at 28.5°C and other temperatures, retrieve embryos from wells, read the signal in individual fish, and output data into an Excel spreadsheet format. Such an automated system must be able to distinguish between spurious maternal signal in the yolk and the zygotic signal in different tissues. Several sized screening microplates should also be developed to accommodate different stage embryos (e.g., gastrula vs. pharyngula vs. young larvae) for orientation in a defined orientation (e.g., lateral view) for image capture. If the embryo sorter can simultaneously genotype and score animals, it should be able to detect fluorescence for green, yellow and red regions of the spectrum and other numerous available fluorophores.

2.       Image capture device for embryo high-throughput/high-content microscopy platform to quantify and report a comprehensive set of features such as count, length, area, intensity, and width, as well as general features about the embryo. The application should automatically discard analysis if the embryo is not in an optimal condition (wrong orientation, unhealthy, out-of-focus). Ideally, images of each embryo should be taken at 2.5x magnification, from one field per embryo down to an appropriate organ-sized field, and capture a variable number of optical sections (up to at least ten) through the embryo. The capturing device should have software to automatically stitch images together and score to exclude autofluoresce in the hatching gland and yolk.

Project goals:

The short-term goal of the project is to perform proof-of-principle technical feasibility demonstration of an automated system for sorting embryos and larvae, dispensing test substances, imaging and analyzing zebrafish embryos and larvae. The long-term goal of the project is the development of capabilities for higher throughput assays with ability to automate scoring of a visible marker or visible phenotype that will be available commercially as a standardized, streamlined process.

Phase I Activities and Expected Deliverables:

Phase I activities should support the technical feasibility of the approach. Specific activities and deliverables during Phase I should include:

·       Design and construction of a prototype system(s).

·       Validation of the prototype system(s) with a sponsoring NCRR investigator/laboratory to conduct usability testing. Include funds in budget to present phase I findings and demonstrate the final prototype to sponsoring NCRR investigator/laboratory or evaluation panel.

·       Documentation providing a top-level description of the prototype system design(s), validation protocol(s), and testing results should be provided to NCRR as part of Phase I progress report.

Phase II Activities and Expected Deliverables:

Phase II studies should further refine the technology or strategy and test its effectiveness for incorporation into the research setting in terms of feasibility, cost, sensitivity, and specificity.

The NHLBI plans, conducts, fosters, and supports an integrated and coordinated program of basic research, clinical investigation, and trials, observational studies, and demonstration and education projects. The Institute’s mission includes studies related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, blood, sleep disorders, and blood resources management. Studies are conducted in its own laboratories and by other scientific institutions and individuals supported by research grants and contracts. The NHLBI SBIR program fosters basic, applied, and clinical research on all product and service development related to the mission of the NHLBI.

Recent technology enabling the production of induced Pluripotent Stem (iPS) cell lines has created significant opportunities for the development of new cell lines as products for use as cell-based bioassays such as in screening assays. The technology provides the means to expand the iPS cell lines to the numbers needed for bioassay applications and will enable the derivation of cell lines with specific phenotypic or genetic characteristics uniquely suited to specific assay requirements. Thus, iPS cell lines represent an excellent substitute for improving upon cell-based assays currently carried out with existing lines or limited supplies of primary cells. Basic research studies are needed to obtain sufficient quantities of the iPS cell line to test their suitability and for comparison to existing assay methods. And fundamental research to improve upon the methods used for iPS cell derivation will accelerate all commercial opportunities. The availability of the initial cell lines as products will benefit those investigators utilizing these assay tools in their research as well as serve as prototypes for investigators who may wish to develop new bioassays using iPS cell lines.

The goal of this solicitation is the development and production of new bioassays based on iPS cell technology to be used for research purposes and to be made available to the scientific community. The assays may be designed for basic research applications and potentially for future clinical assays. The derivation and expansion of the cell lines must be well defined and produced under appropriate manufacturing practices and quality control. The cell-based bioassay must be developed and validated including the use of existing assays as comparators. The successful applicant must develop a production plan to commercialize the assay.

Phase I proposals should focus on the development of a well-characterized iPS cell line and bioassay for research applications. Investigations in this phase will involve laboratory research and early scale-up studies.

Phase II proposals shall focus on scale-up and production of a bioassay for distribution. Assay validation will be required.

Because the heart transplant donor pool in the United States is less than 2,500/year, ventricular assist devices (VADs) are the only realistic option for many late-stage heart failure patients. Currently, each year 2,000-5,000 receive VADs to bridge them to a heart transplant or as permanent (i.e. “destination”) therapy. However, the VADs currently available rely upon batteries that, despite recent advances, require frequent recharging, weigh on the order of pounds, and must be carried by the patient. Furthermore, the percutaneous cables used to connect the batteries and device controllers to the VADs provide a site for infection where the driveline crosses the skin. Consequently, the driveline site must be frequently cleaned to reduce the risk of infection.

Offerors will develop novel technologies for delivering power to VADs to successfully improve the quality of life and reduce the risk of infection associated with current methods for delivering power to VADs for chronic circulatory support. Examples of appropriate projects include (1) power and data transmission systems that do not require percutaneous drivelines and (2) innovative power sources which will reduce the size and weight of external batteries and the frequency of recharging them or, preferentially, eliminate external batteries altogether.

Phase I proposals should address initial development and feasibility testing of novel technologies for delivering power to VADs which can be applied to existing or new circulatory support devices. The technologies should have the potential to eliminate external batteries and/or percutaneous drivelines or make substantial improvements over existing power-related technologies for VADs so that the risk of infections is significantly reduced and the quality of life is improved. Preference will be given to proposals for technologies with the potential to eliminate external batteries and/or percutaneous drivelines.

Phase II proposals should be focused on completing the development of the technology such that it can be readily incorporated into circulatory support devices. The work is expected to include in vitro and in vivo studies to demonstrate effectiveness.

Approximately half of the 44 cells that comprise the human respiratory tract still remain partially identified and their function(s) is incompletely understood (Franks et. al. Proc Am Thorac Soc 2008; 5: 763-6)). Suitable technologies are available to identify, sort, purify, culture, and determine cell surface markers or other unique identifying features that permit individual characterization of cell types. It seems feasible to unravel the origins and functional capabilities of lung cells involved in developmental stages of lung growth and in disease. But it will be necessary to generate new reagents that will identify these still incompletely characterized cells in the human lung, permit establishment of cell lines, and facilitate ready isolation from lung tissue.

Much is known already about many important cells in the human respiratory tract, but little is known about the supportive function of structural cells, the para-endocrine effect(s) of lung cells, and the location and functions of stem and progenitor cells that remain quiescent until stimulated to help repair tissue after injury or disease. Cellular functions that suppress or create apoptosis to reestablish normalcy need insight. Several examples are offered representing the three main compartments of the lung:

1.     Among airway cells comprising the large and small airways of the human bronchial tree, the ciliated, columnar, secretory, and basal cells have been well studied, but more knowledge about epithelial stem and progenitor cells along the airways, mucus and ciliated cell interactions, functions of brush cells, and the stimuli from neuro-endocrine cells to affect integrity of the epithelium, all are needed.

2.     In the alveolus, information is considerable about Type I cells, the multiple tasks of Type II cells, and surfactant production and properties, but Type II cell stimulated epithelial to mesenchymal transition is evolving but is not understood as a process leading to lung fibrosis, and the activity of interstitially located fibroblasts to secrete extracellular matrix needs more scrutiny.

3.     The vascular bed of the pulmonary circulation needs study of the endothelial cells populating different locations and the capillary network, and interactions of endothelium with smooth muscle cells and with adventitial fibroblasts need examination.

Thus, special reagents are needed for studying lung cell biology and cells involved in organ development, growth, and disease. Examples of needed reagents include:

1.     Antibodies that will recognize specific cell types and permit separation and recovery of cells from micro-dissected lung tissue.

2.     Reagents to identify proteomic products produced by cells.

3.     Antibodies that recognize cell surface markers that can help identify and track different cell lineages present in airway and alveolar structures.

4.     Specific antibodies to recognize cell surface markers that help to separate out individual cell types from among heterogeneous lung tissue cells.

5.     Reagents that track cellular changes in differentiation as development occurs, track cells that enter latency, and detect signals of re-stimulation or redeployment for repair tasks.

6.     Reagents that characterize and identify “stem” and progenitor lung cells.

Phase I proposals should focus on development of reagents that identify unique cell surface markers or other special structures that would permit extraction of cells, considered to be incompletely characterized or identified, from human lung tissue biopsy specimens, or other lung bio-specimens such as transbronchial biopsy and bronchoalveolar lavage. This should lead to cell separation and establishment of in vitro cell cultures.

Phase II proposals should focus on scale up production of unique reagents for cell separation that can be placed in a repository for use by other investigators by application to investigate lung disease, and to study cell proteomics and other functions.

Identifying cardiovascular risk factors and understanding the contribution of those risk factors for cardiovascular disease is critical. Identifying individuals at very high risk for CVD and aggressive intervention are a critical factor to minimize the population wide CVD burden. Determining low density lipoprotein (LDL) as well as high density lipoprotein (HDL) particle size distribution may provide additional predictive power to LDL or HDL cholesterol measurement alone to estimate an individual’s risk for CVD. Current systems that can quantify the lipoprotein sub-fractions are labor intensive and need long turnaround time and thus are not practical for routine clinical applications.

Offerors will develop novel technologies for accurate, high throughput measurement of lipoprotein sub-fractions and use the developed technology to study the value of diagnostic performance in CVD.

Phase I proposals should address initial development and feasibility testing of novel lipoprotein sub-fraction measurements.

Phase II proposals should focus on the optimization and standardization of the technology and also compare with existing methods. It is expected that the developed technology be used to study the value of lipoprotein sub-fraction measurements in CVD risk assessment.

Research has shown that an individual’s cardiovascular health is improved with daily exercise and a healthy diet, and work productivity benefits from improved health status. Computer-based reminders have been shown to improve compliance with targeted tasks. By combining these two proven techniques, the goal of this solicitation is to improve the cardiovascular health of program participants through the development of a digital messaging service that intermittently sends heart-healthy nutritional tips and activity reminders to workplace computers. The service may send the information through a downloadable program or use ‘real-time’ push-type delivery. Message and prompt options may be personalized at registration.

Messages promoting cardiovascular health may include low-sodium, low-cholesterol and low-calorie food options or recipes (http://dashdiet.org/what_is_the_dash_diet.asp). Rotating dietary prompts may say: “Whole-grain bread or crackers may complement your lunch today”, “It’s time to drink some water” or “Make your snack a piece of fruit; it’s high in vitamins and fiber”. Audio/video demonstrations and/or text box pop-ups can offer suggestions to stretch, move, or engage in other easy-to-complete work-appropriate activities such as simple office yoga or isometric poses. Reminders may say “Get active, save your work and stretch your arms for 1 minute”, or “Reduce your risk for heart disease by making time for exercise; the stairs are a good alternative”.

The target audience includes computer users seeking to improve nutrition and or incorporate heart healthy activities into their day. The service must be 508 compliant and Federal Government IT security systems compatible. The National Heart, Lung, and Blood Institute will beta test the program and remain a recipient of free services after for-profit operations begin.

Phase I proposals should focus on prototype development. Product demonstration should be conducted half way into the contract. Small scale beta testing should be conducted 2/3rds into the contract to demonstrate feasibility.

Phase II should further refine the service, usability, usage metrics based upon continued user testing, menu options and technology, and will demonstrate effectiveness through end user appeal and lifestyle behavioral improvement success rates.

The program should include, but is not limited to:

·       Offering the end user the ability to select the pop-up topic, delivery frequency and appearance.

·       Collecting Phase I metrics to establish user opinion on subject matter, presentation, topic usefulness, program ease of use and general interest.

·       Collecting Phase II metrics to evaluate program success and future directions. 

The release of hemoglobin into the circulation contributes to morbidity and mortality in intense hemolytic states such as sickle cell disease (SCD). Free hemoglobin related vascular reactivity, potentially through nitric oxide scavenging and oxidative stress associated with the iron moiety of heme likely result in pulmonary arterial hypertension, stroke and the acute chest syndrome in SCD. A glucocorticoid induced increase in haptoglobin synthesis in animal models has demonstrated an attenuation of the adverse clinical effects of free hemoglobin. (J Clin Invest [2009] 119:2271-80)

In SBIR Phase I, offerors are requested to establish a technical and scientific approach and demonstrate the feasibility of manufacturing a human plasma derived haptoglobin concentrate that is representative of the known human polymorphisms. The haptoglobin concentrate would be produced from plasma fractionation using established methodologies (such as Cohn or Kistler/Nitschmann methods) that could support scale-up in production to clinically relevant quantities.

The hypothesis to be tested in SBIR Phase II studies is that well-characterized, infused haptoglobin would complex with free hemoglobin and accelerate its clearance by CD163 on macrophages. This clearance should reduce the risk of altered vascular reactivity due to nitric oxide binding and similarly, reduce oxidative tissue damage mediated by heme iron. These possible effects will be tested in SBIR Phase II studies including a dose escalation safety study in human volunteers including determination of biomarkers which, if successful, could be followed by a trial to examine a dose response for painful events and/or the acute chest syndrome as clinical endpoints in individuals with SCD.

Magnetic resonance imaging (MRI) has the potential to guide non-surgical cardiovascular interventional procedures because it can visualize soft tissue, guide positioning of therapeutic devices, and assess treatment outcome, all without ionizing radiation. To ensure that such procedures can be carried out effectively and safely it is essential to have devices (catheters, guidewires, etc.) that have the appropriate mechanical properties and that are conspicuous (visible) on the MRI images. The only general way to ensure conspicuity is by making the devices active, i.e. by making the devices capable of receiving NMR signals. Unfortunately, such devices (with conductive structures) can heat up considerably in a standard MRI scanner and this is one of the current major obstacles for MRI guided interventions.

The problem of heating of conductive structures during MRI extends to other applications such as imaging of patients with pacemakers and implantable defibrillators. A solution to this problem would have wide implications for the ability to scan a growing population of patients with implanted devices.

It has become clear that one of the key causes of active device heating is electrical coupling between the main MRI scanner transmit system (the body coil) and the devices. This coupling can be eliminated (or greatly reduced) by using a surface coil transmit system, which uses much smaller transmission coils than the main body coil of the scanner. There are two competing constraints that make it challenging to implement such a solution: a) For this solution to be effective the RF transmission system should illuminate the smallest possible area needed to effectively guide the procedure, and b) It may be necessary to follow devices over relatively large distances in the body. To accommodate both of these constraints we envision a surface coil transmit-receive array consisting of a relatively large number of smaller coil elements (i.e. 32, or more elements) covering the entire torso front and back (from the groin to the neck region). The system should allow dynamic activation and deactivation of coil elements such that only a subset of the transmit elements in the region of interest are active at any given point in time.

Specifications

·       The coil array should cover the entire torso approximately 35 cm wide by 60cm long and the area illuminated by the transmission system at any given time should be controllable down to a size of 15x15 cm.

·       It has to be possible to use the system with an MRI scanner without parallel transmit capability, i.e. the system has to be driven by a single RF waveform specified by the sequence. The system could include additional amplifiers and control hardware and software as needed.

·       It should be possible to turn elements on and off dynamically. We envision a programmable interface that can be controlled from the MRI sequence environment.

·       Ideally, it would be possible to control the phase of the RF pulse in each individual transmit element. Element-by-element RF amplitude control would also be desirable to enable dynamic RF shimming as needed to accommodate different body shapes and also to mitigate device heating through more advanced techniques.

·       Multiple receive elements (~16 elements) must be active within the illuminated area to enable parallel imaging acceleration.

·       The NHLBI currently uses 1.5T Siemens MRI systems and the proposed transmit-receive system must be compatible with these scanners (more details will be made available upon request).

Deliverables

Phase I should aim to provide a working prototype system that would allow a) MRI imaging with sufficient image quality to guide an interventional procedure , and b) comprehensive heating testing with interventional devices developed at the NHLBI. Heating test will be conducted in phantom and animal experiments at the NIH in collaboration with on-site scientists.

Phase II will incorporate design changes based on Phase I testing and deliver a complete transmit-receive system, which is safe for patient use. Specifically, the device should be eligible for designation as a “non-significant risk device” by FDA or the vendor is expected to obtain an “Investigational Device Exemption” from the FDA.

In the United States computed tomography (CT) currently accounts for approximately 15% of all diagnostic imaging procedures. The number of CT scans has seen a threefold increase in the two decades leading to 2007 due to its unique capabilities. A CT scan produces high resolution, volumetric rendition of internal organs in a short period. CT scanners are relatively compact and economic to operate and maintain. Thus, they are widely available even in difficult environments. However, CT technology offers relatively low visibility (contrast) of soft tissue structures when compared to magnetic resonance imaging, and at the cost of exposing the patient to substantial ionizing radiation.

In the past few years there has been intense development of the concept of phase-contrast CT, a promising strategy to improve soft-tissue visibility and lower radiation dose by tenfold or higher over conventional absorption-based technology. To translate the phase-contrast concept to clinical applications, the technology must meet a number of requirements, including the ability to work with compact x-ray tubes, fast imaging speed and large field of view, and compact instrumentation. Full-field imaging techniques that utilize x-ray transmission gratings are prime candidates for eventual clinical applications due to their speed and adaptability, but they have not delivered the theoretically possible performance to-date. The main obstacle has been the inability to produce gratings of less than 1 micrometer periods for hard x-rays.

A promising technology to overcome the above limitation is vapor deposition of alternating high and low atomic number layers with layer thicknesses in the sub micrometer to nanometer range. The resulting multilayer structure serves as transmission gratings of extremely small periods when used in the transmission configuration. The concept has been proven effective in x-ray focusing optics. An additional advantage of this technology is that the grating depth-to-period ratio is unlimited in principle, making it effective for hard x-rays employed in animal and human CT. However, current multilayer x-ray transmission optics are fabricated on smooth substrates, while phase-contrast CT presents the need for deposition on patterned substrates in order to achieve sufficient grating areas for CT scanners. Therefore, the aim of this solicitation is to develop fabrication techniques of multilayer structures on patterned substrates to effect large-area, hard x-ray transmission gratings.

Specifications

This solicitation encourages the development of a directional deposition technology of multilayers of alternating high and low atomic number materials on periodic echelle (staircase like) substrates to form large-area x-ray gratings. Deposition rates of 200 nanometer per minute or higher are desired to permit total multilayer thicknesses of tens of micrometers in reasonable deposition time. The packing density of the layers should approach bulk materials for the purpose of effectively modulating the intensity and phase of hard x-rays used in animal and human CT scanners. The thickness and geometry of individual layers should be precisely controlled and uniform over the desired grating area. The directionality of the technology should be sufficient to target specific surfaces of the patterned substrates while avoiding deposition on other surfaces. Deposition protocols for material pairings of tungsten/silicon, chromium/silicon and titanium/silicon should be developed. Proper adhesion of the multilayer structure to the substrate should be achieved without spontaneous delamination. Individual layer thicknesses of approximately 50 nanometers and structurally uniform coated areas of 60mm x 60mm should be developed for small animal CT at 35 keV. Ultimately the technology should be extended to large area gratings for human CT scanners at 60 – 100 keV.

Deliverables

Phase I proposals should focus on the development of multilayer deposition technology of material pairings of tungsten/silicon for absorption gratings and chromium/silicon and titanium/silicon for phase gratings. The targeted x-ray energy is 35 keV for small animal CT scanners. The proposals should aim to achieve individual layer thicknesses of 50 nanometers, total deposition thickness of up to 100 micrometers, and structurally uniform coated areas of 60 mm x 60 mm. Techniques should be developed to selectively deposit on specific facets of the patterned substrate while minimizing material deposition on other surfaces. The substrates for coating tests will be provided by Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health (DIR/NHLBI/NIH). The proposals should also include evaluation of the multilayer structures with cross-sectional electron microscopy either independently by the contractor or with the help of DIR/NHLBI/NIH.

Phase II effort should focus on scaling up the technology developed in Phase I to larger grating areas and total deposition thicknesses of over 100 micrometers for human computed tomography.

Magnetic resonance imaging (MRI) has potential to revolutionize minimally invasive surgery and interventional procedures by affording improved tissue visualization without conventional surgical incisions. Many such procedures will be conducted under both X-ray and MRI guidance. Such procedures require high fidelity hemodynamic recording of physiological signals such as electrocardiography and invasive blood pressure, with seamless bidirectional transfer between X-ray and MRI. To date there are no suitable commercial solutions.

A wireless telemetry system would allow acquisition of hemodynamic signals (multichannel electrocardiography, invasive blood pressure, noninvasive hemoglobin saturation, temperature, etc.) safely in both the MRI and X-ray fluoroscopy environments, and allow continuous monitoring during transportation between the two.

Specifications

The system must conform to the following specifications:

·       The system must operate safely at MRI field strengths of 1.0T to 3.0T.

·       The system must record and transmit signals with the patient inside the magnet bore during imaging.

·       The system should filter MRI-specific noise (e.g. radiofrequency pulses and gradient switching) and be robust to a range of rapid pulse sequences with continuous duty cycle, including single and multi-slice real-time, three-dimensional gradient echo, balanced steady state free precession, and (non-real-time) turbo spin echo techniques. The system must be able to filter noise from low frequency events, such as spoiler gradients or magnetization preparation sequences.

·       The system should provide ten electrodes for diagnostic electrograms (four limb, six chest) under an X-ray environment and at least six (four limb, two chest) under an MRI environment. The electrode and lead system should be safe for operation under MRI, resistant to inadvertent loop formation, and should be radiolucent for operation under X-ray.

·       The system should allow transduction of two simultaneous channels of invasive blood pressure from fluid-filled catheters, ideally with commonly used clinical invasive blood pressure transducers.

·       The system should measure continuous noninvasive hemoglobin oxygen saturation.

·       All physiological signals should be aggregated in a single unit for wireless telemetry. Signals must be received in at least one base station in each modality, (one in X-ray and another in MRI), with automatic handoff from one to the other. Base stations should connect to popular commercial hemodynamic recording systems (specifically Siemens Sensis and General Electric MacLab).

·       The system should provide for uninterrupted operation for at least 6 hours.

·       The system should NOT generate radiofrequency noise that interferes with MRI. The system should not interfere with common commercial Bluetooth and other common radiofrequency patient physiologic telemetry systems used during MRI.

Proposals to address electrocardiogram artifacts from magnetohydrodynamic effects are welcomed but not required.

The sponsoring NIH laboratory is willing to provide access to acquired physiological signals without preprocessing; alternatively the offeror should have access to such a laboratory independently for development and for testing.

Deliverables

The Phase I deliverable is a working prototype to support investigational X-ray and MRI guided interventional procedures in patients. This includes ten ECG leads for use in X-ray and at least six ECG leads for use in MRI, two invasive pressure transducers, and hemoglobin saturation.

The Phase II deliverable is a commercial-grade clinical system.

Mechanical stents to relieve obstructive cardiovascular lesions could have great utility in pediatric cardiology, but are unsuitable for small children. Commercially available stents limit vessel growth and require future surgical removal. Absorbable stents might revolutionize the treatment of congenital heart disease in children. Small children require small delivery systems for devices that are larger than adult coronary arteries. Specific target diseases include aortic coarctation and pulmonic stenosis, which currently require open surgical repair or multiple X-ray-guided catheter procedures in early childhood.

Specifications

These are transcatheter stents to be delivered using conventional interventional cardiovascular techniques including guiding catheters or sheaths, translesional guidewires, and balloon-expandable or self-expanding delivery systems. Conventional and novel approaches are welcomed.

Specific requirements of the stents include small delivery systems (5-6 French or smaller); sufficient radial force to resist elastic recoil for the two applications; sustained radial strength suited to the application for at least 3-6 months; controlled degradation within 6-9 months; inflammatory response that does not cause significant stenosis, restenosis, or aneurysm; resistance to downstream embolization or toxicity; and nominal calibers suitable for the most common lesions (pulmonary artery stenosis and aortic coarctation, see below) .

Proposed stent nominal geometry should be diameter (6-8mm), length (range 10-25mm), delivery system (5-6 French or smaller). The radial hoop strength of the deployed device should approach that of commercial balloon-expandable stent such as the Cordis Palmaz Genesis. Percutaneous vascular access routes for the pulmonary artery application include femoral and jugular venous. Percutaneous vascular access routes for aortic coarctation application include transvenous-transeptal antegrade and retrograde transfemoral artery. The implant or the delivery system should be conspicuous under the intended image-guidance modality.

Deliverables

At the conclusion of Phase I, a candidate device design should be selected for clinical development based on in vivo performance of a mature prototype resembling a final design.

At the conclusion of Phase II, the offeror should obtain an investigational device exemption (IDE), and a supply of devices provided, for a first-in-human research protocol, involving at least 10 subjects, to be performed by the sponsoring NHLBI laboratory. The sponsoring NHLBI laboratory is willing to perform in vivo proof-of-principal experiments in swine, is willing to collaborate toward design of the clinical protocol, and is willing to provide clinical research services. The vendor is expected to perform or obtain safety-related in vivo experiments and data to support the IDE.

Catheter-based ablation therapy is used to treat cardiac rhythm disorders. MRI may have value in targeting and assessing ablation lesions interactively during catheter based cardiac electrophysiology (EP) procedures. Real-time MRI EP ablation may be especially attractive to ablate mid-myocardial targets causing ventricular tachycardia in adults and children.

While technically feasible, there are no commercially available flexible catheter devices to perform EP ablation that are conspicuous and safe under real-time MRI guidance. Such technology, if commercialized, would enable novel treatments for ventricular tachycardia.

Specifications

The offering resembles a “conventional” deflectable multipolar catheter used to perform EP ablation procedures in geometry and in mechanical performance. These must be specified.

The offering must be conspicuous during MRI at 1.5T using “profiling” techniques such that positive contrast is provided along the entire intravascular device shaft and tip. The preferred catheter design for profiling is “active” such that the offering incorporates an intravascular MRI coil that allows the device and tissue to be imaged simultaneously. Alternative designs will be considered that provide high conspicuity during MRI.

The device must be able to obtain multi-channel local intracardiac electrograms. Suitable filtering functionality must be provided to connect the system to a commercial clinical EP recording and mapping system.

The device should be suitable for transcatheter endocardial application and for transthoracic intrapericardial epicardial application.

The device must be capable of radiofrequency ablation of ventricular myocardium during uninterrupted magnetic resonance imaging, which may require appropriate filtering. Alternative ablative energy sources may be proposed. Saline irrigation, or alternative target tissue cooling, should be integrated into the ablation system.

The device should interoperate during MRI with at least two other similar catheters that provide multipolar electrogram recording capability.

The offeror should consider capabilities to perform ventricular defibrillation in the MRI environment. The offering should operate with the interventional MRI system of the sponsoring NHLBI laboratory. The NHLBI currently uses 1.5T Siemens MRI systems and the proposed transmit-receive system must be compatible with these scanners (more details will be made available upon request). The offering must be “MRI safe” or “MRI contingent” to allow future clinical procedures, without heating or local magnetic field disruption according to accepted industry standards and should be designed for safety in a clinical environment. Control of the system should be possible from a bedside operator and from a console-based operator outside the radiofrequency MRI system shield. The system should not generate radiofrequency noise that interferes with MRI at 1.5T. The system should be safe for operators and patients inside and near the magnet bores. The system should not interfere with common commercial Bluetooth and other common radiofrequency patient physiologic telemetry systems used during MRI.

Deliverables

At the conclusion of Phase I, a candidate device design should be selected for clinical development based on in vivo performance of a mature prototype system nearing final design lock.

At the conclusion of Phase II, the offeror should obtain an investigational device exemption (IDE), and a supply of devices provided, for a first-in-human research protocol, involving at least 10 subjects, to be performed by the sponsoring NHLBI laboratory. The sponsoring NHLBI laboratory is willing to perform in vivo proof-of-principal experiments in swine, is willing to collaborate toward design of the clinical protocol, and is willing to provide clinical research services. The vendor is expected to perform or obtain safety-related in vivo experiments and data to support the IDE.

The NIAAA supports research on the causes, prevention, control, and treatment of the major health problems of alcohol abuse, alcoholism, and alcohol-related disorders. Through its extramural research programs, the NIAAA funds a wide range of basic and applied research to develop new and/or improved technologies and approaches for increasing the effectiveness of diagnosis, treatment, and prevention. The NIAAA also is concerned with strengthening research dissemination, scientific communications, public education, and data collection activities in the areas of its research programs.

Efforts to develop medications for alcohol use disorders have expanded rapidly in recent years. Developing novel compounds for alcohol treatment is high priority for NIAAA Medications Development Program. Three agents directed at the addictive behavior in the use of alcohol —disulfiram, naltrexone, and acamprosate—are now approved for use in the United States and many other countries. Recently, topiramate has also been shown to be effective in treating alcohol-dependent patients. Still, these medications do not work for everyone. Because of this, further research is ongoing to develop more alcohol medications, perhaps producing medications that are more effective or at the very least, providing more choices for patients, similar to the situation for the treatment of depression with multiple antidepressants.

During the past decade, many new targets in the brain and liver have evolved that alter alcohol-seeking and drinking behavior. Brain effects and behavior may be influenced by agents directed at CRH1, adrenergic, opioid kappa, vasopressin V1b, NK1, orexin, NPY, NOP, glutamate mGluR2/3, mGluR5, GABAa α-1 and α-5 receptors. Several intracellular targets in additional (peripheral) organs have also been identified that alter outcomes of chronic alcohol use, including ALDH-2; PKC; PPARg; epigenetic modulators, (HDAC inhibitors, methylases, demethylases, and microRNAs); rapamycin complex 1; and GDNF. Tissue damage induced by the influence of alcohol or acetaldehyde on any of the above have serious negative consequences including development of steatohepatitis, cirrhosis or hepatocellular carcinoma.

Specific areas of research include high-throughput screening for novel compounds, drug optimization, efficacy testing, GMP manufacturing, formulation, pharmacokinetic testing, and IND-directed animal toxicology. Any one of the following examples represents an area of interest to NIAAA but proposals are not limited to the examples given:

·       Develop preclinically novel compounds that prevent or reduce drinking.

·       Develop preclinically novel compounds that reduce or eliminate any of the multiple downstream negative consequences of alcohol use.

·       Develop medications to reduce smoking in alcohol-abusing individuals.

·       Develop novel medications to treat alcohol-induced organ damage by attenuating or reversing the tissue damage. Identifying new targets for drug development based on mechanisms underlying the alcohol-induced damage is encouraged.

·       Screen available libraries of approved drugs for repurposing of drugs for any of the above indications.

·       Advance personalized medicine by employing approaches of pharmacogenetics, sophisticated modeling of human characteristics, brain imaging and physiological and biochemical markers.

·       Evaluate combinations of medications to increase efficacy with minimal side effects.

Deliverables would be periodic technical reports on the progress and activities carried out under these R&D contracts, final reports for Phase I and Phase II, and a summary of salient results including the results of all in vitro and in vivo testing in cells, animal and humans where applicable.

The NIDDK supports research in diabetes, endocrinology and metabolic diseases; digestive diseases and nutrition; and kidney, urologic and hematologic diseases. For additional information about areas of interest to the NIDDK, please visit our home page at http://www.niddk.nih.gov.

NIDDK investigators have discovered and are evaluating the first potent and efficacious small molecule agonist of the thyroid-stimulating hormone (TSH, thyrotropin) receptor (TSHR) that has potential for clinical application in patients with thyroid cancer. This agonist drug is intended for use in patients for 2-5 days at a time following thyroidectomy and at subsequent intervals after initial treatment, when radioactive iodine screening is performed to detect the presence of remaining thyroid cancer cells.

Small molecule agonists and antagonists for G protein-coupled receptors (GPCRs) make up approximately 40% of the drugs currently in clinical use. The TSHR is a GPCR. The investigators have shown that this compound is active in model cell systems over-expressing TSHRs, in “normal” human thyroid cells (thyrocytes) in primary culture and, perhaps most importantly, after oral administration in mice to increase iodide uptake in the thyroid gland, similar to the protocol used for administration of recombinant human TSH (rhTSH, Thyrogen®, Genzyme Corporation) to patients with thyroid cancer. The ultimate goal is to see that an easily produced, orally administered, safe and effective drug is developed, launched, and used as an alternative to rhTSH in patients with thyroid cancer world-wide.

This invention is the subject of PCT Application No. PCT/US2008/011958, U.S. Application No. 13/125,045, and foreign counterpartsin Europe, Japan, India, Canada and Australia (HHS Reference Number E-284-2008/0).

Project Goals:

The goal of the project is to obtain a full characterization of the small molecule TSHR agonist to support the filing of an IND application. The investigators have completed optimization for potency and selectivity using in vitro cAMP assays, have performed an SAR with the scaffold, have shown that one of the lead compounds is effective after oral administration in mice and have had 1 gram of a highly purified, active preparation of the compound synthesized. The investigators have recently determined the half-life in mouse plasma, the protein binding in mouse plasma and the degradation of the agonist by mouse liver microsomes. The investigators propose performing the following prior to the beginning of this contract: identification of the major metabolites and determination of their activities; pharmacokinetics in mice after intravenous, intraperitoneal and oral dosing of the parent compound and the major metabolite with measurements of their tissue concentrations; activity measurements in mice (including the major metabolite) with efficacy testing; and pharmacology in mice including cardiac, pulmonary and neurologic (hot plate) testing.

During the contract period the following will be performed in rats and dogs: determine pharmacokinetics and bioavailability; dose range finding; genetic toxicology; safety pharmacology; toxicology studies; and histology/pathology assessments. NIDDK will schedule a pre-IND meeting with the FDA and begin work on a formulation for administration to humans. If funded, we do not envision any roadblocks to accomplishing these steps.

This is an NIH TT (Technology Transfer) contract Topic from the NIDDK. This is a new program whereby inventions from the NIDDK Intramural Research Program are licensed to qualified small businesses with the intent that those businesses develop these inventions into commercial products that benefit the public. The contractor funded under this contract Topic shall work closely with the NIDDK inventor of this technology who will provide continuous guidance for the work performed by the offeror and perform in vitro laboratory analyses to support development of the agonist by the offeror. The inventor will provide assistance in a collaborative manner during the entire award period. Between the time this contract topic is published and the time an offeror submits a contract proposal for this Topic, no contact will be allowed between the offeror and the NIDDK inventor. However, a pre-submission public briefing and/or webinar will be given by NIDDK staff to explain in greater detail the technical and licensing aspects of this program.

The awarded contractor will automatically be granted a royalty-free, non-exclusive license to use NIH-owned and patented background inventions only within the scope and term of the award. However, an SBIR offeror or SBIR contractor must negotiate an exclusive or non-exclusive commercialization license to make, use, and sell products or services incorporating the NIH background invention. An SBIR contract proposal will be accepted as an application for a commercialization license to such background inventions. Under the NIDDK NIH TT program, the SBIR contract award process will be conducted in parallel with, but distinct from, the review of any applications for a commercialization license.

Model licenseagreements are available at http://www.ott.nih.gov/forms_model_agreements/forms_model_agreements.aspx#LAP. Certain terms of the model license agreement are subject to negotiation. Please contact the designated NIH Licensing and Patenting Manager (Tara Kirby, Ph.D., 301.435.4426, tarak@od.nih.gov) with further questions.

Licensing procedures will comply with Federal patent licensing regulations as provided in 37 CFR part 404. A further description of the NIH licensing process is available at http://www.ott.nih.gov/licensing_royalties/intra_techlic.aspx. NIH will notify an SBIR offeror or SBIR contractor who has submitted an application for an exclusive commercialization license if another application for an exclusive license to the background invention is received at any time before such a license is granted.

Any invention developed by the contractor during the course of the NIH TT contract period of performance will be owned by the contractor subject to the terms of Section 8.5.

Phase I Activitiesand Expected Deliverables:

·       Synthesize andevaluate activity of non-GMP drug in HEK293 TSH receptor cells and in primary cultures of retro-orbital fibroblasts provided by investigator.

·       Conducttests* in rats and dogs to determine pharmacokinetics and bioavailability.

·       Conductdose range finding* in rats and dogs with serum measurements of T₃, T_4, and thyroidal radioiodine uptake.

·       Conductgenetic toxicology* in rats.

·       Conductsafety pharmacology* in rats.

·       Conducttoxicology* studies in rats for 5 days.

·       Conducthistology/pathology* assessments in rats.

·       Conduct Pre-IND meeting with FDA.

*Note: Conduct as non-GLP or GLP as appropriate.

·       Provide resultsof all studies.

Phase II Activitiesand Expected Deliverables:

A Phase II proposal will typically/generally only be invited by NIDDK if the Phase I contractor has been granted a commercializationlicense via the process described above.

·       Conduct genetictoxicology in dogs.

·       Conduct safetypharmacology in dogs.

·       Conduct toxicologystudies in dogs for 5 days.

·       Conduct histology/pathology assessments in dogs.

·       Develop formulation for administration to humans.

·       Prepare IND application.

·       Provide resultsof all studies.

NIDA’s mission is to lead the nation in bringing the power of science to bear on drug abuse and addiction, through support and conduct of research across a broad range of disciplines and by ensuring rapid and effective dissemination and use of research results to improve prevention, treatment, and policy.

It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded.

Assessing the results of clinical investigations of pharmacotherapies for treating drug abuse is made difficult by the lack of certainty that patients have taken the prescribed treatment as instructed. Negative outcomes of trials of pharmacotherapies might be due to the failure of patients to comply with the treatment. The outcomes of clinical trials are then uncertain, damaging the reliability of expensive clinical testing. Traditional bioassays (urinalyses of drug metabolites) are time-consuming and expensive. Therefore, NIDA seeks an accurate method/technology of compliance monitoring that is less expensive than bioassays and delivers monitoring results in a timely manner.

The technologies/products should allow patients to take experimental medications by the oral route in situations that are not supervised by clinical staff members (e.g. at home) yet provide relevant study staff with accurate, nearly real-time, knowledge of patient-specific compliance, thus allowing timely interventions that can correct noncompliance. It is envisioned that a flexible, multi-platform, mobile system could allow clinical researchers to accomplish the goals stated here.

Proposals concerning bioassays or biochemical testing methods are not of interest and will be deemed not responsive to this funding announcement. Systems requiring custom drug product formulation as an essential component of system operation are not of interest.

Phase I Activities and Expected Deliverables

Develop and test the feasibility of a prototype system demonstrating the following:

·       Create new or adapt existing sensor or sensor system for detection of medication ingestion by a given patient. Examples may include video, voice or some combination of wearable psychophysiological measure sensors which in combination reliably indicate medication ingestion by the oral route.

·       Create software as needed for reliably and securely storing data on the device as required.

·       Create software as needed for reliable and securely transmitting sensor data to investigators including participant ID, time & date.

·       Adapt existing database solution for reliable and secure storage and management of collected data compatible with mainstream data analysis solutions typically used in treatment research (e.g. Excel, SAS, or SPSS etc…).

·       Create reliable and secure software solution for notifying patient and clinical trials staff of non-compliance within 6 hours and integrate it with a physical means of notifying the patient of non-compliance (e.g. patient wearable device, patient cell phone or study phone issued to the patient for use in the trial).

·       Develop or adapt existing solution to verify patient identity; this may include developing tools for data analysis (such as image identity verification from sensed data) or peripheral tools such as a wearable RFID tag placed on the patient in the clinic and which will only permit transmission of data when the sensed data is within close range of the RFID (and hence is coming from the patient).

·       Feasibility: test the software and hardware on patients in the lab receiving a medication and gather preliminary data on the reliability of the system and its ease of use by research staff and patients.

Phase II Activities and Expected Deliverables

Develop and validate a production model prototype by using the system in patients undergoing treatment with an FDA approved medication for treating addiction such as buprenorphine.

Addiction to cocaine is a serious health problem in the U.S. (currently estimated by the U.S. Office of National Drug Control Policy at 3 million individuals). Untreated cocaine dependence significantly increases health, social service, and criminal justice costs to society and is a major vector contributing to the spread of infectious diseases such as HIV, TB, and hepatitis. To date, there is no FDA approved medication for the treatment of cocaine dependence. Responding to the need for effective therapies, the National Institute on Drug Abuse (NIDA) supports research and development activities regarding the preclinical and clinical aspects of pharmacotherapies for the treatment of cocaine dependence.

One of the candidate drugs to treat cocaine dependence is the mGluR5 antagonist fenobam. It is postulated that fenobam may be useful in the treatment of cocaine addiction because mGluR5 antagonists have been shown to affect four cocaine-induced processes thought to be important in the development of, and relapse to, cocaine addiction: 1) decrease in cocaine self-administration in rodents and in monkeys; 2) blockade of cocaine-cue induced drug seeking behavior; 3) blockade of cocaine-primed reinstatement in an animal model of cocaine self-administration; and 4) blockade of the acquisition of cocaine place preference in rodents. In addition, mGluR5 antagonists have shown efficacy in animal models of the same processes related to nicotine.

NIDA is planning to test fenobam for safety and efficacy in the treatment of cocaine dependence. As fenobam is an investigational compound which has not yet been approved for marketing in the United States, the development and manufacture of an appropriate oral dosage form of fenobam will be undertaken by NIDA. NIDA is, therefore, soliciting proposals for a SBIR contract for the development and manufacture of a solid oral dosage form (tablets or capsules) of fenobam under GMP conditions that will be used in IND-enabling non-clinical and Phases I/II clinical studies for the treatment of cocaine dependency. Fenobam is an insoluble drug in water and in common aqueous pharmaceutical solvents. There are very limited information on pharmacokinetics and pharmacodynamics of fenobam. Offeror is expected to develop a physically and chemically stable oral dosage form that demonstrates appropriate in vitro dissolution profiles and in vivo bioavailability in dogs and other appropriate animal models

Phase I Activities and Expected Deliverables

Offeror is expected to show the feasibility of solid oral dosage form(s) by demonstrating improved and optimized in vitro dissolution profiles of fenobam by applying pharmaceutical tools such as solubilization, complexation, solid solution, self-emulsifying delivery system (SEDDS), nanotechnology, etc. The offeror needs to develop methods for chemical assay of fenobam and in vitro dissolution at pH 1 and 7.4.

Phase II Activities and Expected Deliverables

Offeror is expected to formulate a prototype formulation(s) based on feasibility studies in Phase I and to perform bioavailability studies in dogs and in other appropriate animal models. The offeror is also expected to optimize the formulation(s) based on in vitro dissolution and bioavailability data in animals. The optimization process may be iterative. The offeror is expected to manufacture a GMP scale-up batch and to complete a CMC documentation for IND. The Phase II activities are summarized below:

1.       Prepare prototype formulation(s).

2.       Perform in vitro dissolution and in vivo bioavailability studies.

3.       Optimize the formulation(s).

4.       Collect stability data.

5.       Manufacture a GMP batch.

6.       Prepare product specifications.

7.       Prepare Certificate of Analysis.

8.       Prepare CMC documentations following FDA guidances.

It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded.

Objective: This topic addresses the need for addiction treatment improvement by further developing and expanding an evidence-based therapy for use with in-treatment addicted populations through development of a commercializable and compelling game to be played over an “off- the- shelf” commercially available gaming system that can sense and be controlled through user body motions. Examples of systems at the time of this writing eligible for inclusion are the Nintendo Wii, the Sony Playstation Move and the Microsoft Xbox Kinect. The project will involve programming a “seek and destroy”- type of virtual interactive active game where patients find and use a variety of fun body movements over a natural user interface to eradicate virtual drugs, alcohol, and or cigarettes and related stimuli. The project may, depending on the console selected, also involve development of peripherals for use with the system.

Background

Recent research by Girard et al (2009) has shown that 4 sessions performing behaviors, incompatible with smoking cigarettes (crushing virtual cigarettes), within a virtual environment was more efficacious for smoking cessation than a similar game in which patients found and crushed virtual balls. The mechanism of this treatment is not well understood and it may be a form of extinction, counter conditioning, exposure with response prevention, or re-evaluative conditioning. Nonetheless, such virtual practice in a “game” environment may be uniquely helpful because it can deliver a large “dose” of alternative practice in a manner that people not just tolerate but also enjoy. The fact Girard et al’s short duration gaming experience could improve outcomes in comparison with a “placebo” control suggests that games which involve the body in alternative practice may hold great promise for treating addiction.

Active, interactive videogames (AIVs) utilizing movement sensitive gaming consoles such as the Nintendo Wii, the Playstation Move, and the Xbox Kinect offer the opportunity for a substance abusers or smokers to put his/her entire body into the process of creating new sense memories with respect to substance-related cues. The opportunity to practice not responding automatically to such cues along with the opportunity to use many different muscle groups has potential to create new brain patterns that may disrupt old automatic behavior and emotional patterns and ultimately reduce relapse.

In addition to enhancing treatment effects for addiction and smoking cessation, AIVs may also be a form of health promotion to the extent that they get participants exercising. A prime barrier to smoking cessation attempts is fear of weight gain. An AIV-based treatment that increases large muscle group movement, thereby increasing metabolism and thereby reducing weight gain in smokers afraid to quit because of fears of weight gain is a further selling point for such a system.

One of the biggest challenges with both addiction and smoking cessation treatment is getting people to try existing treatments. Research indicates that many smoking quit attempts proceed without treatment, and less than 6% of quitters try both behavioral and medication treatment despite availability of recommended by experts approaches. Addiction treatment utilization is poor as well with the majority of substance dependent people never accessing treatment. Novel treatments that appeal to people to enter and re-enter treatment and to stay in while enrolled may have dual benefits from both their own unique mechanism of action as well as by boosting exposure to the benefits of traditional treatment. Research has shown that tangible incentives improve outcomes of traditional treatments but they have been criticized for a lack of practicality and sustainability. It may be possible to use access to a novel treatment such as a videogame similarly, as an incentive for participating in or using a traditional treatment. The following scientific opportunity involves creating a highly engaging game which may have independent treatment effects and which when used in conjunction with traditional addiction and/or smoking treatment may help improve treatment engagement to leverage traditional treatment benefits.

Phase I Activities and Expected Deliverables:

·       Modification of an existing game or development of a new therapeutic game for Wii, Move or Kinect, in which one or several participants hunt for and destroy virtual drug, alcohol, and/or smoking stimuli and paraphernalia using bodily movements sensed and recorded by the game;

·       Development of peripherals for to interact with the game as needed;

·       The game should include the opportunity for patients to select the substances that are most relevant to them or allow them to play a “multi-drug version” of the game if they need to address multiple substance use;

·       The game should make use of a variety of body movements (e.g., stomping, shooting, batting, hurling, squashing etc…) to enable the participant to “virtually” destroy target substances as a way to “get clean” or win the war on their substance(s);

·       The game should offer a variety of environments similar to those where addictive substances are used (urban neighborhood, bar, party), in which the patient can practice refusal skills as well as opposing practice;

·       The game should include a variety of difficulty levels of increasing intensity and allow for up to 4 hours of gameplay;

·       The game may include challenges in which participants refine skills for example, tossing the drug accurately into a trash receptacle that becomes smaller at each level, or kicking them through a goal;

·       The game should be themed to pit the patient’s avatar who is the hero or “recovery warrior” against the substance of abuse;

·       The patient’s avatar should be customizable to produce a likeness similar to the patient so he/she can name and view the avatar as him/herself; gender, height age, facial characteristics, race are some of the desirable customizable features;

·       The game should be able to recognize and keep track of the patient’s performance over time so the patient can experience improvement in gameplay with each episode of practice;

·       The game should record, store, and provide for downloading into a database, information regarding system use by each player such as time played, repetitions of behaviors and types of behaviors used to determine the extent of adherence and the “dose” required;

·       The game may also allow participants to practice of drug refusal skills when faced with virtual drug offers; in games with this feature, virtual offerors should be responsive to the “recovery hero’s” actual body posture, gaze and physical or verbal responses and these should be displayed by the hero and offeror avatars within the virtual game;

·       The game may allow for cooperation and interaction with other recovery warriors when the game is played as a group exercise;

·       A pilot study with a group of adult substance users in treatment (N=9).

o   The study will expose patients newly enrolled in treatment to the game weekly for 30 minutes a session, for 4 weeks.

o   Measures collected at baseline will include weight, drugs of choice, and timeline follow-back.

o   Measures collected following each game exposure session will include acceptability, suggestions for improvement, AES/SAES craving ratings, urine drug screening and cotinine screening (for smokers) and treatment engagement data.

o   Measures collected 1 month after treatment entry will include timeline follow-back.

o   The pilot testing may be done in an iterative fashion so that multiple small focus groups are exposed to the program and it is modified in response to their comments.

Phase II Activities and Expected Deliverables:

Modification of a program, developed in Phase I, in response to customer feedback followed by an RCT Pilot clinical study evaluating the effectiveness of the Recovery Warrior Game. Outcomes collected will include AES, SAEs, treatment engagement information from clinic records, system use information (durations, movements repeated, times accessed) initial abstinence and/or smoking cessation rates via urine screening, smoking quit attempts, and weight changes.

The project objective is to deliver non-viral RNAi vectors to the cytoplasm of a cell type in the brain after systemic administration. Thus, the non-viral shRNAi vector must efficiently cross the blood barrier and efficiently deliver shRNAi to the desired cell type within the brain. After delivery to the target cell, shRNAi must efficiently escape from the endosome into the cytoplasm. The non-viral vector complexed with shRNAi should show no toxicity. Ultimately, the technology developed here will not only be applicable to the treatment of substance use disorder but to other brain diseases as well.

Phase I Activities and Expected Deliverables:

·       Design and create non-viral shRNAi vectors for systemic administration to silence a gene in a defined cell type in the brain in a rodent model. Delivery may be oral, intranasal, intravenous, or intraperoteneal.

·       Demonstrate that the selected gene in the chosen cell type in the rodent brain will be silenced in vivo by systemic delivery of the non-viral shRNAi directed against the selected gene.

·       Demonstrate that an innate or adaptive immune response does not occur in response to chronic administration of the vector.

·       Determine the pharmacokinetics, tissue distribution, and excretion of the shRNAi vectors.

Phase II Activities and Expected Deliverables:

Phase II studies will apply the delivery system created in Phase I to a potential therapeutic target for the treatment for substance use disorders.

For example, changes in G protein signaling have been shown to mediate addiction and relapse of drug seeking behavior. AGS3/GPSM1 activator of G protein signaling in the prefrontal cortex and core of the nucleus accumbens is upregulated during withdrawal following chronic administration of cocaine and heroin. The upregulation of AGS3/GPSM1 increases the amount of AGS3/GPSM1 binding to Giα and decreases the amount of Giα ?to interact with the βγ? G proteins subunits, resulting in sustained ligand-activation of receptors coupled to βγ? G proteins subunits such as mGluR2/mGLuR3, the DRD2 receptor, and the A2 adenosine receptor. Injection of an AGS3/GPSM1 peptide into the prefrontal cortex produced a cocaine sensitized phenotype manifested by enhance locomotor response to acute administration of cocaine. Injection of anti-sense AGS3/GPSM1 oligonucleotides prevented sensitization to cocaine and inhibited cocaine priming of drug seeking behavior by normalizing AGS3/GPSM1 protein levels. Injection of anti-sense AGS3/GPSM1 oligonucleotides into the core but not the shell of the nucleus accumbens also blocked reinstatement of heroin and ethanol seeking behavior. The discovery of the process of RNA interference (RNAi) makes AGS3/GPSM1 a potentially therapeutic target for the treatment for substance use disorders.

·       Implement a strategy to demonstrate that in vivo systemic administration of a non-viral shRNAi vector against AGS3/GPSM1 selectively silences AGS3/GPSM1 in DRD2 BAC expressing transgenic mice.

·       Identify off-target silencing by the shRNAi against AGS3/GPSM1.

·       Demonstrate that an innate or adaptive immune response does not occur in response to chronic administration of the vector complexed with AGS3/GPSM1 shRNAi.

·       Determine the pharmacokinetics, tissue distribution, and excretion of AGS3/GPSM1 shRNAi vectors.

·       Determine the dose response relationship for silencing AGS3/GPSM1 by the shRNAi/AGS3/GPSM1 vectors.

·       Determine the duration of silencing produced by the shRNAi/AGS3/GPSM1 vectors.

·       Demonstrate that systemic administration of the shRNA vector against AGS3/GPSM1 in rats and mice blocks conditioned place preference to cocaine and morphine and blocks the lowering of intracranial self-stimulation (ICSS) reward thresholds by cocaine and morphine.

·       Demonstrate the effective of systemic administration of the shRNAi vector against AGS3/GPSM1 to block intravenous self-administration of cocaine and morphine and decrease the break point for self-administration of cocaine and morphine on a progressive ratio in rats and monkeys.

·       Determine the dose response relationship for shRNAi vectors against AGS3/GPSM1 to decrease self-administration of cocaine and morphine in rats and monkeys.

Determine the duration of suppression of i.v. self-administration of cocaine and morphine in monkeys following intravenous or intraperotoneall injection of the shRNAi vector against AGS3/GPSM1

It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded.

Transmission between injection drug users (IDUs) is a major cause for HIV infection, accounting for around 25% of HIV new case. Highly active anti-viral treatment (HAART) is an effective treatment for HIV infection, and probably also effective in lowering the chance of HIV transmission among IDUs. However, poor adherence to lifelong HAART treatments, especially among IDUs, long-term side effects, and other factors dampen the effectiveness of chronic HAART. In addition, the therapy cannot eradicate the latent, low-level HIV reservoirs in patents.

When HAART is withdrawn from a patient, rapid HIV rebound occurs quickly. It is currently believed that a shorter-term, non-lifelong treatment that can achieve drug-free remission should be the new goal of HIV treatment. Patients with this type of treatment eliminate completely HIV completely from reservoirs in the body and would therefore alleviate the associated risk of spreading HIV through shared needles amongst IDUs.

Lentiviral-based gene therapy represents an optimal short-term treatment option that would eliminate all HIV viruses from the body. Whereas several research groups/companies have employed this strategy to deliver multiple small-hairpin RNA (shRNA)/therapeutic components, all of them use ex vivo delivery methods and there is evidence that this approach does not eradicate the latent HIV reservoirs in patents.

New strategies such as in vivo delivery of Lentiviral-based multiple highly-potent small-interfering RNA (siRNA) and naturally-enveloped proteins of HIV could be developed to effectively treat more effectively HIV-infected IDUs especially those with latent reservoirs.

The burden of HIV and hepatitis C virus (HCV) co-infection is quite significant. In the United States, 15-30% of subjects infected with HIV are co-infected with HCV. Thus, NIDA also seeks the development of microRNA clusters designed to simultaneously inhibit several steps of the HCV cell cycle by specifically targeting various segments of the HCV gene as well as host cell companion proteins. This “cluster attack” on the HCV genome may particularly benefit human subjects who are co-infected with HIV and HCV because of the more severe nature of their disease and their more limited therapeutic choices. Combinatorial therapies, based on miRNAs, delivered via lentiviral vectors, may overcome the genetic barrier of concomitant and frequent HCV mutations. For example, the microRNA-mediated IFN-mimetic effect on the HCV cell cycle may deliver the on-target effects of IFN in the liver while avoiding the off-target effects of IFN in other tissues and organs.

Phase I Activities and Expected Deliverables

·       Design and construction of potent shRNA vectors and in vitro assessments.

·       Vector Packaging and Characterization.

·       Assays for Inhibition of Gene Expression.

Preliminary Toxicity Testing

It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded.

A need exists to understand the genetic bases of tobacco addiction and related disorders. Advances in research supported by the National Institute on Drug Abuse (NIDA), and other NIH Institutes have identified several thousand genetic variants related to tobacco dependence. Given that genetic variants identified through these research programs, the research community is poised to take advantage of genetic technology that would allow researchers to use a single uniform platform for screening genetic variants related to substance abuse, and more specifically to tobacco dependence and related disorders.

The technology exists to develop a customized “out of the box” Smokescreen to screen thousands of an individual’s genetic variants at once. Development of this Smokescreen for tobacco dependence and related diseases would advance the understanding of the (1) genetic vulnerability to tobacco dependence, (2) gene variants related to co-morbidity, including risk and/or treatment approaches for other addictive and psychiatric disorders, peripheral artery disease, chronic obstructive pulmonary disease, and lung cancer, and (3) genetic profile of the patients for targeted treatments (i.e., pharmacogenetic approach).

Major limitations to studying how these genetic variations may be incorporated into personalized approaches for smoking cessation in the clinic include: 1) the small numbers of samples available from participants who have participated in clinical trials studying medications for treating tobacco addiction, 2) the lack of a universal and validated screening tool for data collection, and 3) the lack of a centralized database for storing and analyzing the information into usable knowledge that clinicians and researchers studying tobacco addictions, its treatments and its consequences would reference.

This SBIR contract solicitation provides an opportunity to address these limitations. NIDA has identified a set of genetic variants that will allow the development of a uniform set of genetic variants to be screened. The overall goal is to encourage eligible small businesses to develop a genetic screening tool to profile specified genetic markers that may be related to smoking dependence and to smoking treatment, taking into consideration that the profiles of dependent smokers may be different than profiles of smokers responding to treatments for cessation. NIDA has established a prioritized set of genetic markers for developing the Smokescreen as described in: https://nidagenetics.org/neurosnp/neurosnp_about.html.

In order to collect clinical data for tobacco dependence and smoking cessation, a universal genetic “Smokescreen” is needed as a research tool for use in a wide variety of clinical settings, such as clinical trials, community treatment programs for smoking cessation, clinics specializing in tobacco additions, and researchers studying tobacco addictions, medications for cessation, and consequences of tobacco addiction.

A single genotyping or sequencing based platform for the genetic “Smokescreen” will be enriched for candidate SNPs/genetic regions that will provide a fourfold benefit to the clinical and scientific community: i) It will enable researchers to more accurately and reproducibly compare genetic variant data across studies; ii) it will provide a more focused and targeted SNP analysis that leverages existing knowledge; iii) it will be enriched with SNPs and/or targeted genetic regions from multiple ethnicities to allow for allele frequency differences and rare variations across populations, and iv) it will provide a resource for developing personalized approaches to pharmacotherapies for smoking cessation treatments and possibly other related co-morbidities, including risk and/or treatment approaches for other addictive and psychiatric disorders, peripheral artery disease, chronic obstructive pulmonary disease, and lung cancer.

The Smokescreen will provide patients and physicians with more information about the prospects for the smoking dependence risk (and possibly the other co-morbidities listed above) and it will support treatment decisions. The Smokescreen is envisioned to be used in conjunction with a nicotine metabolite ratio (NMR) test, as the NMR will likely be a better measure of smoking dependence. However, the Smokescreen may provide additional data for targeting cessation therapies by profiling or stratifying participants in clinical trials for smoking cessation medications, and may also be helpful for determining risk of potential consequences of heavy smoking, such as lung disorders and lung cancers.

Phase I Activities and Expected Deliverables

Prototype the Smokescreen for use in basic and clinical research settings with the most recent genetic technology available and using the prioritized genetic variants recommended by NIDA in https://nidagenetics.org/neurosnp/neurosnp_about.html (genotyping chip or new sequencing approaches such as MySeq from Illumina)

·       Develop prototype Smokescreen that is “out of the box”

·       Include a prototype approach for collecting the data and storing it for analysis, such as interfacing with a free, publicly accessible, central database for storing and analyzing the data with a user interface that is easy for upload and download of data, and create a database for researchers and clinicians to store and analyze the data from its use broadly, such as PharmGkb, GeneGo, Neuroscience Information Framework (NIF), or an alternative that integrates and expands the knowledge obtained from the use of the Smokescreen

·       Analyze the basic and clinical research market for potential consumers of the Smokescreen

Phase II Activities and Expected Deliverables

Market and Manufacture the Smokescreen

·       Market the Smokescreen for basic and clinical research use.

·       Based on the market analysis, generate enough Smokescreens to be used for an initial phase of use to establish usability in terms of ease of use, data submission, cost and applicability in different research settings.

·       Describe the necessary evidence that will be needed to validate the Smokescreen as a potential tool for use in a variety of indications, such as: smoking dependence risk, smoking cessation medications best suited for a given profile (combined with NMR), and risk for other diseases related to smoking.

·       Develop methodologies that will:

o   Establish profiles that can be tested as to whether they predict smoking dependence, as well as smoking cessation;

o   Establish profiles that can be tested as to whether they predict other addictive and psychiatric disorders, peripheral artery disease, chronic obstructive pulmonary disease, and lung cancer.

Market the Smokescreen for clinical application

It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded.

Drug overdose is currently the second leading cause of unintentional death in the United States, second only to motor vehicles crashes. The population at risk for opioid overdose is diverse and includes, for example, more than 3% of U.S. adults currently receiving long-term opioid therapy for chronic noncancer pain, in addition to drug/substance abusing population. Opioids are now more often being prescribed for patients with moderate to severe pain.

Thus, effective measures that would prevent/avert opioid overdoses are needed as overdoses and death often occur inadvertently in private settings where no one is present to offer assistance. Furthermore, patients with opioid addiction are prone to overdose on injected opiates or on excessive oral doses of opioid medications. These overdoses also often happen when no help is available and patient’s lives are at risk.

The objective of this project is to develop an automated device that would administer standard doses of naloxone to a patient in overdose, thus reversing the effects of excess opiate. Naloxone has been used for decades in medical settings to avert opioid overdose, and recent pilot programs demonstrated the feasibility of proper use of naloxone by non-medical personnel. Patients expressing physiologic signals of opiate overdose (e.g. hypoxia, respiratory rate below a critical threshold for a critical period of time, etc.) could be administered an appropriate dose of naloxone even if unconscious. Due to the short duration of action of naloxone, the unit should be capable of repeating the injection after resetting itself and detecting another set of critical information.

There are more than 300,000 heroin users, nearly 5 million prescription opiate users, plus millions of chronic pain patients receiving end-of-life opiate analgesic pain care. The number of poisoning deaths and the percentage of these deaths involving opioid analgesics increase each year. From 1999 through 2006, the number of fatal poisonings involving opioid analgesics more than tripled from 4,000 to 13,800 deaths. Potentially, everyone who has been prescribed opioids, for pain or addiction, and heroin users, could be offered this device by their treatment provider who may be an addiction specialist, primary care physician or pain doctor. There is a crucial need to provide this device to these populations to prevent unintended overdose and deaths and to address public health need.

Phase I Activities and Expected Deliverables

·       Design the prediction algorithm for opioid overdose requiring the intervention and establish the endpoints for algorithm development

·       Design and assemble a prototype of detectors, injector and supporting hardware

·       Propose a strategy to prevent un-indicated use, such as in a person who is unresponsive due to the reasons other than an opioid overdose

·       Field-test the prototype with focus group participants.

Phase II Activities and Expected Deliverables

·       Conduct the initial clinical testing in appropriate user population which is sufficiently powered to adequately inform Phase II

·       Develop detailed plans for initial production model with cost projections

·       Plan regulatory approval strategy

·       Establish an FDA-compliant system

Conduct clinical testing necessary for FDA approval

It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded.

Drugged driving is a signature issue, one of the three top issues, of President Obama’s 2010 Drug Control Strategy. Recently released NHTSA data from the 2007 National Roadside Survey of 7,500 daytime and nighttime drivers, including survey questions and oral fluid and blood samples, showed that 11% of samples had detectable levels of illegal drugs and 5% had medications. Several studies in the United States and European countries found that at least 35% of people stopped for erratic driving, drivers involved in a crash, and fatally injured drivers had at least one drug in their system, and many were under the influence of both drugs and alcohol. Marijuana is the most prevalent drug, after alcohol, found in samples from drivers involved in traffic accidents or stopped for impaired driving. Those and other released data have alerted the research community of the problem’s magnitude and the urgency of addressing it.

Major effort to address the drugged driving problem will have a significant effect on the demand for drugs and on drug use in the United States. However, this effort is being impeded by multiple factors: 1) lack of available or quality data to adequately understand the magnitude of the problem and its possible solutions; 2a) lack of prevention strategies specifically tailored to drugged driving; 2b) lack of understanding of ways to tailor existing effective strategies to address drugged driving; 3) lack of treatment interventions to address the problem, other than from a criminal justice perspective: 4) lack of effective policy approaches to address the patterns of drugged driving problems.

This SBIR Contract solicitation seeks to address a need for more and better quality data on drugged driving and, therefore, seeks proposals to develop web-based systems that can allow for efficient access to and utilization of data on drugged driving, and allow public and private organizations and officials to locate, plan, implement and evaluate the effectiveness of prevention and intervention strategies to address the problem of drugged driving and its associated consequences. Responses to this solicitation can consider ways to adapt existing systems that compile, organize and assess quality data and implementation approaches. They may also design completely new web systems to accomplish these goals.

The web systems proposed in response to this solicitation should provide a repository of necessary information and resources for researchers and policy-makers to utilize. Some of the core research questions to address through this scientific initiative include the following areas.

Data and measurement-specific questions:

·       What data are currently available?

·       How are these data collected?

·       What are the important gaps in the currently available data?

·       What strategies will help to fill these gaps?

·       What methodologies could be used to improve the quantification of drugs?

·       What standard screening methods can be developed for drug-testing laboratories?

Intervention-specific questions:

·       What prevention or treatment interventions currently exist that directly address drugged driving?

·       What existing prevention or treatment interventions that do not currently address drugged driving can be adapted to address drugged driving issues?

Policy-specific questions:

·       How can the health care provided to individuals involved in drugged driving accidents be better managed?

·       How can data and effective strategies be used to encourage states to adopt more effective drug laws?

·       Which professional audiences need adequate information and training and what is the best way to provide this training? Examples might include law enforcement personnel, prosecutors, judges, health and education professionals, community practitioners, and parents and other family members.

Phase I Activities and Expected Deliverables:

1)       Assemble a consultant team to determine available data sources and intervention strategies in regards to drugged driving.

2)       Propose a prototype design for a web system to manage drugged driving data and to promote selection of appropriate prevention and intervention strategies.

3)       Build a prototype for feasibility testing.

4)       Conduct feasibility tests with a diverse array of professional audiences (less than 10 participants per professional group) – law enforcement, health professionals, and policy-makers. Focus group or user testing are possible approaches, but bidders are encouraged to be creative in their suggested approaches.

5)       Analyze and report data.

6)       Develop plan for Phase II activities.

Phase II Activities and Deliverables:

Pending positive results of Phase I design and feasibility testing,

1)       Complete web-based tool.

2)       Collect law enforcement and medical/health data to include in web-based tool.

3)       Conduct a randomized study with professionals representing the target audience for the tool, primarily law enforcement, medical/health professionals and policy-makers, but also may include educators, service providers and others, to assess the tools ability to:

a.     Capture relevant and useful drugged driving data.

b.     Provide prevention and intervention information and other resources.

c.     Provide tools for the selection and implementation of prevention and intervention strategies.

d.     Provide information and other resources for assessment of implemented strategies.

e.     Capture and reassess trends in drugged driving data.

4)       Close-out activities

a.     Analyze and report findings.

b.     Engage strategic partners for commercialization.

c.     Begin implementation of commercialization strategy.

The Center for Global Health (CGH) leads the execution of the CDC’s global strategy; works in partnership to assist Ministries of Health to plan, manage effectively, and evaluate health programs; achieves U.S. Government program and international organization goals to improve health, including disease eradication and elimination targets; expandsCDC’s global health programs that focus on the leading causes of mortality, morbidity and disability, especially chronic disease and injuries; generates and applies new knowledge to achieve health goals; and strengthens health systems and their impact.

CGH Internetsite:  http://www.cdc.gov/globalhealth/

During the past decade, several companies have developed lateral flow immunochromatographic devices to detect antibodies to individual communicable diseases. More recently, these platforms have also been adapted to detect specific antigens associated with these infections. These inexpensive point-of-care (POC) tests offer considerable advantages over conventional laboratory tests, since they can be performed in remote, peripheral settings with little or no instrumentation by primary health care workers. In addition, counseling and treatment, if appropriate, can be given at the initial consultation. They have been used successfully to screen pregnant women for HIV and syphilis to prevent vertical transmission of these infections and therefore prevent congenital disease. In addition, in areas remote from formal, organized blood banks, these and other POC tests have been used to screen potential blood donors to prevent transfusion related infections. Unfortunately these tests are usually performed as individual tests for antibodies or antigens for single infections, which results in a series of test strips being run in parallel. Each may have different flow characteristics, buffers and run times which can lead to confusion and potential inaccuracies.

Project Goal:  The goal of this project is to develop a highly sensitive, highly specific, rapid and easy to use, disposable multiplex immunochromatographic screening device to detect Hepatitis BsAg and malarial antigen together with antibody to Human Immunodeficiency Virus 1 and 2 (HIV 1/2) and syphilis in a single finger-stick sample of whole blood in order to screen pregnant women to prevent vertical transmission of infection. In addition, a single device to detect Hepatitis BsAg and malarial antigen together with antibody to Hepatitis C Virus (HCV), Human Immunodeficiency Virus 1 and 2 (HIV 1/2) and syphilis in a single finger-stick sample in order to screen blood donors for transfusion- related infections in settings where conventional laboratory facilities are not available.

Vendors should have access to existing individual immununochromatographic tests to detect antibody to HIV, HCV and syphilis and tests to detect HBsAg and malaria. Likewise, vendors should be prepared to optimize their assays to detect both antibodies and specific antigens in the same cassette device on a single specimen. The contractor will be able to leverage this research and development opportunity to build capacity within the company to develop further multiplex platforms with antigen/ antibody combinations of diagnostic value. The CDC is willing to collaborate with small business by furnishing appropriate specimens to enable optimization of the multiplex platform and to facilitate both laboratory evaluations to be conducted within CDC laboratories in Atlanta and clinical evaluations in appropriate field sites in settings where these infections constitute a significant public health problem and where the tests would ultimately be used routinely.

Impact:  It is anticipated that the development of these two multiplex immunochromatographic test cassettes could result in a significant reduction in rates of congenital HIV and syphilis together with other infections that can be transmitted from mother to child. In addition, make blood transfusions safer in areas where laboratory testing is either not available, or of poor quality.

Babesiosis is a potentially life-threatening zoonotic disease caused by intraerythrocytic protozoan parasites, which usually are tick-borne but are also transmissible by transfusion. Most infections are asymptomatic or only causemild disease but severe disease can occur in neonates, the elderly and immunocompromised patients. Babesiosis became nationally notifiable in January, 2011.

Blood transfusion transmission of babesiosis, a healthcare acquired infection, has been recognized as an important source of infection and disease and is currently the most frequently reported transfusion acquired disease in the United States. Asymptomatic individuals are difficult to recognize and, therefore, transfusion of blood and blood components collected from them may result in transfusion-transmitted babesiosis (TTB), leading to potentially fatal clinical illness. Babesiosis is associated with significant morbidity and mortality. Increasing numbers of cases of TTB and TTB-associated deaths have been reported in recent years. In July, 2010 the Blood Products AdvisoryCommittee of FDA strongly supported implementation of regional blood donor screening for Babesia microti infection. Currently, no blood donors screening test for babesiosis has been licensed and available diagnostic test formats are not suitable for the high throughput testing required for blood donor screening.

Project Goal:  The goal of this project is the development, validation, and FDA clearance of a high-throughput method for Babesia- specific antibodies with sensitivity and specificity equal to or greater than the existing gold standard method, the indirect immunofluorescence antibody assay, which is labor intensive and not suitable for high throughput blood donor screening. An effective and feasible test must be compatible with existing blood donor screening platforms, which require rapid results and flexibility to accommodate large numbers of samples tested simultaneously. Other innovative non serological approaches that can be easily integrated into existing blood donor screening platforms and workflows would also be considered. All submissions must include validation and FDA clearance as deliverables.

Impact:  Reliable blood donor screening for babesiosis will prevent transmission by transfusion and decrease the number of deaths attributable to this healthcare acquired disease. This would preserve the blood supply since other options for controlof this transfusion transmissible disease include stopping blood collections in risk areas for months when tick-borne transmission is occurring. Introduction of blood donor screening for babesiosis will help improve blood safety and prevent healthcare acquired disease, in keeping with CDC’s goals. CDC will collaborate with test developers to validate tools in the field and to disseminate new technologies.

The mission of the CDC’s National Center on Birth Defects and Developmental Disabilities (NCBDDD) is to promote the health of babies, children and adults and enhance the potential for full, productive living. To achieve its mission, NCBDDD works to: Identify the causes of birth defects and developmental disabilities; helps children to develop and reach their full potential; and, promotes health and well-being among people of all ages with disabilities, including blood disorders.

NCBDDD Web site:  http://www.cdc.gov/ncbddd/index.html

Many neural tube defects (NTD), serious birth defects of the brain and spine, can be prevented if a woman consumes folic acid daily before and during early pregnancy. Although mandatory folic acid fortification has increased blood folate concentrationsin the U.S., folate insufficiency remains a severe problem on a global scale. Determining the burden of folate insufficiency in a population can help set the stage for large-scale interventions such as food fortification. However, lack of data on blood folate levels hampers public health efforts to identify, intervene, and evaluate populations at risk for NTDs. In addition, many countries have remote and isolated populations, making population-based testing of blood folate levels challenging due to limited access to appropriate laboratories. Dried blood spots (DBS) might be adapted to assess folate status in the field, but use of this technique for collecting, storing, and analyzing folate levels quickly and effectively has not been established.

Project Goal:  The goal of this project is to develop technology to measure blood folate levels, and specifically to develop: 1) an assay that can be used ‘on the spot’ in fieldwork either using DBS or whole blood, or 2) an assay in which the sample is collected in the field and analysis is done in a laboratory within 48 hours.Additional specifications are that 1) the instrument needs to be portable and low maintenance, so it can be used directlyin the field; 2) the maximum volume needed should not exceed 50 uL of blood from a finger stick; 3) the imprecision of the assay should not exceed 10-15% at the clinical decision point of 140 ng/mL of red blood cell folate; and, 4) the assay results have to be comparable to traditionally accepted assays, such as the microbiological assay.

Impact:  The global burden of folate insufficiency as it relates to NTDs has not yet been determined, but is estimated to be over 200,000 pregnancies yearly. This gap in data is primarily because large-scale national surveillancestudies of folate levels and NTDs have not been possible in many countries. Additionally, many countries have remote areas where access to appropriate laboratory facilities is limited or available laboratories have limited capacity for biological testing. An assay that can add data on folate status from remote areas to a country’s surveillance system can allow for an accurate burden of disease estimate. Developmentof these new assays would provide the means to document the folate status of target populations and help determine a course of action to address folate insufficiency programmatically. The expectation is that the proposed technology will meet market demand by laboratories and in-the-field research groups.

The mission of the National Center for Emerging and Zoonotic Infectious Diseases aims to prevent disease, disability, and death caused by a wide range of infectious diseases. NCEZID focuses on diseases that have been around for many years, emerging diseases (those that are new or just recently identified), and zoonotic diseases (those spread from animals to people). NCEZID’s work is guided in part by a holistic “One Health” strategy, which recognizes the vital interconnectedness of microbes and the environment. Through a comprehensive approach involving many scientific disciplines, NCEZID can attain better health for humans and animals and improve our environment.

NCEZID’s Web site:  http://www.cdc.gov/ncezid

The Vaccine Adverse Event Reporting System (VAERS) serves as the nation’s frontline early warning system to detect vaccine safety concerns. To enhance and sustain reporting efficiency and improve data quality during routine and emergency situations, recent efforts have been made to advance the VAERS web reporting interface and increase web-based reporting. Although web-based reporting can be done with handheld devices and smartphones it is cumbersome and time consuming. The project goal therefore is the development of application software (app) that will help providers readily complete a VAERS reporting form from a smartphone or other device that will be uploaded instantly to the VAERS system.

Currently, more than 200 million mobile apps are used by doctors and patients, and more than 600 million medical apps are projected to be used by 2012. A free app for the FDA’s adverse drug reaction reporting system, “MedWatch”, has already developed and marketed to health care providers and the public to facilitate reporting to MedWatch. With the rapid development of apps and increasing use and popularity of smartphones by health care professionals, an app to facilitate reporting to VAERS would likely be well accepted. This innovation relates to two CDC strategic public health priorities: 1) better prevent illness, injury, disability and death by enhancing the overall vaccine safety monitoring system and thereby keep vaccines as safe as possible and 2) strengthen surveillance, epidemiology, and laboratory services. Moreover, it also addresses the 2011 National Vaccine Plan goal to “enhance the vaccine safety system.”

Project Goal:  The goal of this project is the development of a smartphone application (e.g., iPhone, iPad, Android) that will allow a healthcare provider to instantly link to a VAERS reporting form that is user-friendly and is submitted to the VAERS central database rapidly and securely. This project is a proof of concept study that an app for smartphones can enhance reporting by providers. The VAERS app can include the reportable event table, links to other Web sites and general information about vaccine safety. The results of this project have the potential to increase reporting for clinically important vaccine adverse events since it will target clinicians.

Further dissemination would require additional development to make the app compatible with other smartphones or devices. Collaboration with marketing venues will be necessary to make this app widely available (e.g., iTunes). Adding a link to download this app to multiple provider Web sites such as the American Academy of Pediatrics, American Academy of Family Physicians and others would be appropriate to widely disseminate and encourage adoption of this innovative technology.

Impact:  This work will improve data quality, timeliness of data acquisition and data processing and augment (i.e., increase reporting from clinicians) the vaccine safety monitoring system that contributes to the assessment of risk from vaccinations and helps the Advisory Committee on Vaccine Practices (ACIP) and CDC make evidence-based recommendations for the use of vaccines. Enhanced reporting to VAERS will make this surveillance system a more robust and responsive public health tool for monitoring potential adverse event signals and lead to enhanced vaccine safety monitoring capacity.

Fungi are some of the most common causes of major HIV-related opportunistic infections in the world. Cryptococcal meningitis is estimated to kill more HIV-infected persons than tuberculosis in sub-Saharan Africa. Pneumocystis pneumonia is the most common cause of acute pneumonia in most areas; histoplasmosis is extremely common in Central and South America, and penicilliosis marneffei is highly endemic in Southeast Asia. Prevention of serious sequelae (meningitis, respiratory failure, bloodstream infection) and death in these patients depends on prompt diagnosis and treatment. However, in many resource-poor areas, diagnosis of these infections is not possible because diagnostic tests are not available.

Project Goal:  The goal of this project is the development of rapid, simple, affordable laboratory tests that are designed to be used in resource-poor settings to diagnose these diseases, and to distinguish them from other non-fungal diseases with similar symptoms. Such tests are feasible: a lateral flow “dipstick” test for Cryptococcus is in development and shows promise.

Rapid fungal diagnostics is an area that should be of particular interest to small business concerns. Laboratories in developing countries have either no alternative methods, or only elaborate and inefficient methods, to diagnose fungal infections at this time. The developed assays should have the characteristics of simplicity and robustness as described by the World Health Organization. Innovative approaches such as “dipstick” technology that can be used in the clinic and the field are already being employed in areas such as malaria diagnostics, showing proof-of-concept. Such rapid fungal diagnostics can be incorporated into resource-poor countries as laboratory capacity-building efforts develop and continue.

Impact:  Rapid point-of-care tests can reduce deaths, hospitalization, and other serious sequelae (including immune reconstitution syndrome) among HIV-infected persons by differentiating these diseases from other clinically similar ones, thereby allowing for appropriate therapy. The primary benefit of such diagnostics is in resource-poor countries where HIV incidence is high, but market opportunities also exist in the United States where these fungal infections also occur in high-risk patient populations.