HHS STTR RFA-HL-15-026

Background

Twenty-five years after discovery of the gene that causes cystic fibrosis (CF), we now are witnessing the emergence of drug therapies that target the fundamental molecular dysfunctions associated with mutations in the CF transmembrane conductance regulator (CFTR) gene. While these novel therapies offer an exciting prospect for modifying disease outcomes in CF, they may complicate even more the difficulty of deciding which treatments to use in which patients. The future choice of which drugs to use in an individual patient will likely be a formidable challenge given the multiplicity of known genetic defects, the variety of therapeutic strategies being developed, the likelihood that patients will benefit from multiple drugs administered concurrently, the remarkable heterogeneity of outcomes among patients who share the same genotype, and the large variation in cost among treatments. This escalating challenge of how to select individual treatments in CF highlights the necessity for novel diagnostic tools that could be used to predict responses of particular patients to particular treatments. The present initiative will support up to 4 Phase I Small Business Technology Transfer (STTR) grants focused on development and testing of novel in vitro human cellular models to predict individual responses to CFTR-directed therapeutics. Phase I STTR grantees can get Phase II funding by applying as a SBIR using the companion funding opportunity RFA-HL-15-027 .

Two lines of investigation now are converging to allow development of novel diagnostics for precision medicine in CF. The first is the established utility of cultured cell models to reflect clinically relevant biological consequences of CFTR mutations. Proof of this concept is exemplified by the development of ivacaftor, a drug initially identified by high-throughput screening with an in vitro cultured human cell model of CF subsequently shown in human trials to substantially impact clinically important outcomes. We postulate that human cellular models that have proven valuable for identifying drugs for treating CF can be adapted to test individual responsiveness to these drugs.

A second line of investigation that should enable development of in vitro CF diagnostic tools is productive research advancing methods for maintaining and controlling cell properties in vitro. Investigators have recently developed a variety of powerful methods, including techniques for large-scale expansion of human epithelial cells from a small biopsy/tissue brushing and for producing conditionally reprogrammed cells, adult stem cells, and induced pluripotent stem cells. Technical advances in this area reduce a major barrier to testing CFTR therapeutics in patient-specific airway cells with particular CFTR mutations.

While the primary goal of this initiative is to promote precision medicine and optimization of treatment at the personal level, it may also yield as a secondary benefit the ability to select appropriate treatments for CF at an earlier age. With the advent of genetic tests that allow physicians to screen all newborns, CF is routinely identified a few weeks after birth, before lung symptoms appear. As a result, researchers can now explore the earliest stages of CF lung disease, monitor disease progress over time, and potentially choose the most appropriate interventions before lung damage becomes irreversible. The in vitro models developed through this initiative might theoretically be used to predict clinical treatment outcomes among young children before their pulmonary disease is manifest, leading to a paradigm shift from symptom-based treatments to earlier interventions intended to delay or prevent the onset of disease.

Research Objectives

This funding opportunity announcement (FOA) encourages Phase I Small Business Technology Transfer (STTR) Grant applications from small business concerns proposing research for commercial development and validation of novel in vitro human cellular models for predicting the responses of individual patients to CFTR-directed therapies for cystic fibrosis (CF) lung disease.

Proposed research projects are expected to focus on the development of highly innovative cell-based systems that recapitulate a patient-specific CFTR phenotype to create a personalized study platform to examine response to CFTR-directed therapeutics. The models developed must be based on live cells from humans harboring CFTR mutations associated with CF. However, applicants are allowed considerable flexibility in how those cells are harvested, processed, and grown and in how the effects of therapeutic drugs are assayed. Investigators are encouraged to take advantage of recent advances in epithelial cell culture, which have defined effective methods for greatly expanding the numbers of cells and redifferentiating functional cell types to obtain an airway phenotype that is reflective of the native epithelium (e.g., cell polarity, ion transport, formation of ciliated cells and mucus secretion). Investigators may also wish to explore new opportunities for studying effects of CF therapeutics in organotypic 3-D cultures (e.g., bronchospheres). Preclinical data indicate that these cultures predict ion transport efficacy of CFTR potentiators and correctors on a group-wide basis and support their use as a tool to predict efficacy on an individual patient level.

Because studies of humans will be required, small business applicants are encouraged to partner with academic medical institutions experienced in clinical care of patients with CF and conducting research on the patients' disease and respiratory cell biology. The in vitro systems developed in this research must faithfully replicate disease-relevant properties of airway epithelial cells. At a minimum, investigators will be expected to characterize the reproducibility and intra- and inter-individual variations of in vitro responses and correlate in vitro data with the baseline clinical characteristics (including sex) of the donor subjects. In addition, validation studies, comparing in vitro responses to a particular drug with clinical outcomes in donor subjects receiving that drug, may be feasible if cells are derived from subjects previously or currently enrolled in clinical trials testing CFTR-directed therapeutics. Limited animal studies are allowed, but only to the extent necessary for the initial development and validation of cellular models.

Phase I STTR grantees can apply for Phase II funding by submitting to the SBIR companion funding opportunity RFA-HL-15-027 .

Specific Areas of Research Interest

Research examples appropriate for this FOA include, but are not limited to, those listed below:

• Characterize the functional and microanatomical properties of airway epithelial cell culture systems to assess their potential as tools for predicting responses to CFTR therapeutics.
• Use innovations in cell culture systems (induced pluripotent stem cells, adult stem cells, conditionally reprogrammed cells, air-liquid interface cultures, organotypic 3-D cultures, etc.) to optimize their usefulness as model systems to test CFTR-directed therapeutics and predict drug actions and patient responses.
• Explore the mechanistic underpinnings of drug response in cultured cell systems to improve the performance of in vitro measures of drug effect.
• Use novel imaging approaches in concert with measures of physiologic function to detect and track abnormalities in CF animal and in vitro cellular models and assess therapeutic response.
• Conduct proof of concept studies in humans (adolescents and adults allowed, but with particular interest in studies in young children) to validate in vitro cellular model studies as model systems for CFTR-specific therapeutics.

Projects Outside the Scope of this FOA:

The following types of applications are not responsive to this FOA and will not proceed to review:

• Technologies to generally improve human cell culture models.
• Technologies that only use non-human cells/models.
• Development of in vitro cell-based systems that would not lead to person-specific responses to CFTR-directed therapeutics.