Organotypic Culture Models developed from Experimental Animals for Chemical Toxicity Screening (R43/R44 Clinical Trial Not Allowed)

This FOA solicits Phase I (R43), Phase II (R44), Direct to Phase II (R44) or Fast-track (R44) SBIR grant applications from SBCs to develop novel, engineered 3-dimensional or organotypic in vitro systems using cells from experimental animal models typically used for toxicology testing (e.g., rat, mouse, rabbit, or dog) that will replicate biological responses within the corresponding animal tissues or organs and can provide alternatives to animal testing. These models are called 3D culture or organotypic culture models (OCM) and can include more complex microphysiological systems. When developed and validated, these non-human animal-derived in vitro systems will provide information needed to help predict toxicity of chemical and drug candidates, will enable comparisons with existing in vivo animal toxicity data, can serve as a newer assays for toxicology testing, and have the potential for reducing the numbers of animals used in toxicology testing. These in vitro systems will also enable comparison with human cell-based OCMs and improve confidence in human cell-based in vitro models that use similar technologies. Background The National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), within the Division of the National Toxicology Program at NIEHS, supports the development and evaluation of method for replacement or reduction of animal use in toxicity testing, including the development and evaluation of new, revised, and alternative methods to identify potential hazards to human health and the environment https://ntp.niehs.nih.gov/pubhealth/evalatm/index.html. The development of alternative in vitro organotypic models for drug development and toxicity screening through programs such as the NIH/NCATS Tissue Chip program, https://ncats.nih.gov/tissuechip, has the potential for meeting NICEATM goals of reducing animal use as well as reducing the cost and effort of drug and toxicant screening through the development of validated organ-on-a-chip systems for safety testing. However, these systems are currently developed primarily using human cells. A critical enabler for building confidence in human-relevant test systems is an understanding of how to mechanistically, phenotypically, and quantitatively extrapolate in vitro biology to in vivo biology. Our inability to ethically model toxicity in human subjects prevents us from building that confidence experimentally. Therefore, animal-based in vitro systems that complement our current animal-based in vivo testing are our best opportunity to develop that understanding and move toward a less animal-dependent future. Development of experimental animal OCMs that recapitulate key features of in vivo human biology and outcomes will enable initial screening efforts that reduce the need for extensive in vivo animal studies. In addition, finding concordance between in vitro OCMs and in vivo toxicology results in animals can help to strengthen the confidence in testing results from human OCMs. Therefore, there is a need for development of OCM or 3D culture in vitro systems. The proposed technology and/or product development must use animal cells in the context of OCMs or in vitro 3D cultures. This FOA is not intended to support research using human cells, but the platforms developed may be applicable to human cells for comparison. Objectives Areas of interest and examples of applications that are responsive to this FOA include, but are not limited to development of: •3D tissue, OCM, or microphysiological systems for toxicology testing derived from experimental animal tissues including but not limited to: liver, lung, heart, brain, and kidney. •OCM models derived from embryonic stem (ES) cells or pluripotent stem cells, or from single or multiple cell types, that replicate the biological function and responses of the target organ of interest. •OCM models that assess critical biological targets and or biomarkers that are comparable to in vivo toxicology endpoints. •in vitro models that capture complex cell-cell and cell-extracellular matrix interactions to help link molecular initiating events to chemical risks at the tissue or organ level in an Adverse Outcome Pathway framework. •in vitro models that incorporate metabolism and other critical features of biological responses to toxicants in the target tissue. Additional Considerations One of the goals of this FOA is to strengthen the confidence in both human and experimental animal cell-derived 3D culture models or OCM in predictive toxicology and safety testing. Comparisons between in vivo and in vitro animal studies are encouraged, using existing or retrospective in vivo animal data. However, applicants should not include new in vivo animal studies in their research plan for initial development of these models. Comparisons between human cell and animal-derived OCM, for example, a liver organotypic model, may also be appropriate for this FOA. However, this FOA does not support the development of new human organotypic models. Applicants should propose test chemicals or compounds that are relevant for developing and testing the specific tissue model, and, ideally, include compounds for which species-matched in vivo data already exists to enable in vitro/in vivo comparisons. Materials such as native extracellular matrices or plastics should be carefully selected to avoid for their confounding characteristics due their biological properties, potential downstream effects, undesired binding or leaching effects. Novel matrices that have been developed for human OCM can be modified or adapted for experimental animal-derived OCM. This FOA does not support the development of new human OCMs or microphysiological systems; applications proposing the development of human cell-based OCMs are therefore not responsive to this FOA. Applicants should use ongoing or existing in vivo animal data for comparisons with animal cell-derived OCMs; new in vivo animal studies are not supported by this FOA. Applicants should provide clear, measurable goals (milestones), particularly for Phase I applications and Phase I components of Fast-track applications. See Section VIII. Other Information for award authorities and regulations.