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Methods to Improve Reproducibility of Human iPSC Derivation, Growth and Differentiation (SBIR) (R44 – Clinical Trial Not Allowed)

Description:

Human induced pluripotent stem cells (iPSCs) are somatic cells that have been reprogrammed to an embryonic stem cell-like state such that they are able to differentiate into any cell type in the body. iPSCs and other regenerative technologies have potential to transform clinical practice by creating living, functional tissues to repair or replace tissue or organ function lost due to age, disease, damage or congenital defects. To date, iPSCs have been used with great success to mimic the differentiation of a variety of tissues, understand early development and study human diseases. Despite approaches that have made the derivation, growth and differentiation of iPSCs more efficient, there remains significant variability in reprogramming efficacy, genomic integrity and developmental potential of iPSCs derived from a single fibroblast or tissue sample. Thus, iPSCs derived from the same sample may differ in their in vitro growth characteristics and their ability to re-differentiate into the desired tissue type.

A variety of issues may affect derivation of the iPSCs and their growth, stability and differentiation, including the specific characteristics of the starting cell or tissue sample (e.g., age of donor, tissue type and anatomical location, physiological and disease state), the methods and protocols used to induce pluripotency (e.g., transcription factors, small molecules, cell fusion), the choice of growth factors and other culture conditions, method of storage of cell lines, etc. Further challenges include growing and maintaining sufficient quantities of iPSC lines in culture without changes in their properties, as well as the ability of multiple investigators to identify and authenticate iPSC lines as part of their research.

This FOA addresses the needs of the biomedical research community to improve reproducibility of iPSC derivation, growth and differentiation. It builds on NIGMS’ interest in cell line reproducibility; a FOA, entitled Better Defining Growth Medium to Improve Reproducibility of Cell Culture (SBIR) – PA-18-815, was published in 2018. This FOA is also one of a suite of initiatives planned by many NIH Institutes, Centers, and Offices to support research to develop, demonstrate and validate experimental human tissue models that do not rely on human fetal tissue (NOT-OD-19-042).

This FOA will support SBIR projects that address the needs of developers and users for supporting technologies and products to expedite the development of novel, reliable and cost-effective methods to standardize and increase the utility and reproducibility of iPSCs at all stages, from their derivation to their research and clinical applications.

Topics include, but are not limited to:

  • Methods for more reproducible derivation of human iPSCs
  • Tools to standardize de-differentiation of human somatic cells into iPSCs
  • Specialized methods, tools and products for characterizing and validating human iPSCs
  • Development of protocols that increase fidelity of tissue differentiation from human iPSCs
  • Toolkits to assist users in conducting reproducible research with human iPSCs
  • Methods, tools, and products for growing, maintaining, and authenticating iPSCs

Institute Interests:

NIGMS: NIGMS supports basic research that increases our understanding of biological processes and lays the foundation for advances in disease diagnosis, treatment, and prevention. NIGMS' research mission is aimed at understanding the principles, mechanisms, and processes that underlie living organisms, and does not focus on specific diseases, organ systems, stages of life or populations. For more information see https://www.nigms.nih.gov/about/overview/pages/default.aspx.

NCATS: NCATS intends to fund applications that meet its mission. For a description of the NCATS SBIR/STTR research priorities see https://ncats.nih.gov/smallbusiness/priorities.

NCI: In alignment with the NCI Cancer MoonshotSM priority to advance better research models, the NCI is especially interested in applications for novel tools/technologies that increase the utility and reproducibility of iPSCs that can be used in model systems to advance immuno-oncology research. Specifically, the NCI seeks to support projects that replace the use of human fetal tissue to model the tumor microenvironment with a more faithful representation of the human immune system. Under this RFA, the proposed research projects must address how the iPSCs will recapitulate the tumor microenvironment with appropriate elements of the human immune system derived from iPSCs. Applicants should explain which aspects of the immune system their proposed model is intending to reproduce, and justify why their model would be a reliable or improved alternative for immuno-oncology research to existing human fetal tissue-based models and approaches.

NIAAA: Topics of interest to NIAAA include, but are not limited to: Methods for more reproducible derivation of human iPSCs; Studies using organoids to model development and diseases of specific tissues, ultimately in the context of prenatal alcohol exposure; Studies using organoids to understand tissue-specific functions and how they are impacted by alcohol exposure; Studies to build new technologies that allow for modeling and studying function of multiple tissues at the same time (e.g., integrated “tissues-on-chips” systems); Studies using iPSCs to understand cellular-level mechanistic functions and how they are affected by alcohol exposure.

NIAMS: NIAMS will support SBIR projects to develop novel, reliable, and cost-effective methods to standardize and increase the utility and reproducibility of iPSCs at all stages, from their derivation to their research and clinical applications, for studying and/or treating arthritis, musculoskeletal and skin diseases.

NIDCR: NIDCR intends to accelerate progress in developing robust, efficient and reproducible protocols for reprogramming cells derived from dental, oral and craniofacial (DOC) tissues into pluripotent iPSCs. The goal of this work will be to obtain a collection of high-quality iPSC lines, which would provide a valuable resource for the scientific community. The applicants should employ appropriate technical approaches for cellular reprogramming that will satisfy the requirements for robustness, efficiency and reproducibility and should utilize functional assays to demonstrate the success of these technical approaches. NIDCR is also interested in supporting projects that generate reliable, efficient and reproducible protocols for differentiation of iPSC cells into mature functional cells of different DOC lineages. The applicants should employ functional in vitro and in vivo assays to validate the differentiated phenotype of their iPSC progenies.

NIDDK: NIDDK will support research projects on the development of iPSC for endocrine cell replacement, disease modeling and treatments of diabetic wound healing and diabetic neuropathy

NIDA: NIDA supports research to understand, prevent, and treat substance use disorders and mitigate their consequences to improve the public’s health. For the purposes of this FOA, NIDA encourages iPSC-based methodology and technique development that can reproducibly elucidate and validate cell and neural circuit mechanisms involved in mediating the addictive properties of substances. Of particular interest are reproducible responses in iPSC and/or iPSC derived cells to substances of abuse such as opioids, cannabinoids, nicotine, amphetamine, cocaine, barbiturates, and hallucinogens. The ultimate goals of this research is to understand the brain mechanisms that underlie tolerance, sensitization, and dependence of abused substances to inform future diagnosis, prevention and treatment of substance use disorders.

NIEHS: NIEHS supports the development of complex tissue models derived from induced pluripotent cells that can be used for toxicity testing and characterizing biological responses to toxicant exposures. A key aspect to toxicity testing is the generation of reliable, reproducible iPS cells used to develop organotypic culture models. Another key component is the generation of more “mature” iPSC-derived cell models that recapitulate the cellular and molecular functions of in vivo cells, including epigenetic reprogramming, mitochondrial function, and xenobiotic metabolism.

See Section VIII. Other Information for award authorities and regulations.

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