Industrialization and Translation of Extracellular Vesicles for use in Regenerative Medicine (U43/U44 Clinical Trials Not Allowed)

Purpose This Funding Opportunity Announcement (FOA) invites eligible United States small business concerns (SBCs) to submit Small Business Innovation Research (SBIR) Phase I and Phase II (Fast track and Direct to phase II) grant applications. The funding opportunity will utilize a U43/U44 cooperative agreement to support SBCs to propose the development of novel extracellular vesicle-based therapeutic platforms for use in regenerative medicine. This FOA is focused on the development of platforms associated with the production, manufacturing, and use, of native or engineered EVs as therapeutics. The EV products should have therapeutic applications in the area of tissue and organ repair in regenerative medicine.. Background Extracellular vesicles (EVs) are endogenous membrane-enclosed carriers of bioactive protein, lipids and nucleic acids that are used for intercellular communication. The term, extracellular vesicles, is a generic term used for particles released from the cell that are delimited by a lipid bilayer that cannot replicate. However, there are multiple EVs subpopulations that can be differentiated based on criteria, including: size, biogenesis, release pathways, cargo, and function. EVs are released by virtually all cell types and EV-based intercellular communication takes place during normal cell homeostasis, or as a consequence of pathological development. EVs can cross biological barriers, can be modified to load molecular drugs, have few known deleterious effects and are relatively non-immunogenic, and can maintain their activity during storage. Several NIH programs have supported studies to understand the biology of EVs, and exosomes, and their potential use as therapeutics and diagnostics. This includes the NIH Common Fund's Extracellular RNA Communication Program (https://commonfund.nih.gov/exrna, which aimed to develop novel tools and technologies for the isolation and analysis of single EVs. However, there are a number of challenges in the use of EVs as therapeutics, including, but is not limited to, the production of sufficient quantities of EVs for therapeutic use, labor-intensive EV isolation procedures that are often not compatible with large-scale GMP manufacturing, and non-specific EV isolation methodologies. The goal of regenerative medicine is to regain or restore damaged or lost function of tissues and organs. The NIH Common Fund's Regenerative Medicine program (https://commonfund.nih.gov/stemcells) concluded in 2020 and aimed to accelerate breakthroughs in the development of stem cell-based therapies for complex diseases. In addition to developing a clinical-grade, current good manufacturing practice (cGMP) iPSC line, this program established the Stem Cell Translation Laboratory (SCTL) (https://ncats.nih.gov/stemcell), within the NIH National Center for Advancing Translational Sciences (NCATS) with the goal of bringing induced pluripotent stem cell technologies closer to clinical applications. Despite these successes, major challenges remain in regenerative medicine, particularly in tissue regeneration and repair. There have been numerous studies demonstrating the ability of EVs as potential regenerative entities, particularly for their role in the repair and regeneration of various organs and tissue types. Recent studies have demonstrated that native EVs derived from stem cells, such as mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs), have inherent therapeutic potential. EVs are able to affect cell phenotype, recruitment, proliferation, and differentiation in a paracrine manner resulting in many potential applications in the field of regenerative medicine. Engineered EVs can be loaded with cargo such as small molecule therapeutics, genetic modifications, and surface markers modified for specific therapeutic targeting. Many diseases could benefit from novel EV-based therapeutics. However, this FOA will focus on tissue and organ repair, and wound healing within regenerative medicine to address current challenges in the field, and to harness the advances made in regenerative medicine from previously funded NIH programs. It is anticipated that the use of non-living cellular products, such as EVs, for applications in regenerative medicine will lead to better translation into the clinic. This Funding Opportunity Announcement (FOA) invites eligible United States small business concerns (SBCs) to submit Small Business Innovation Research (SBIR) Phase I and Phase II (Fast track and Direct to phase II) grant applications. The funding opportunity will utilize a U43/U44 cooperative agreement to support SBCs to propose the development of novel extracellular vesicle-based therapeutic platforms for use in regenerative medicine. This FOA is focused on the development of platforms associated with the production, manufacturing, and use, of native or engineered EVs as therapeutics. The EV products should have therapeutic applications in the area of tissue and organ repair in regenerative medicine. The goal for this funding opportunity is to support platform-oriented technology development associated with the production, manufacturing, and use, of EVs as therapeutics in regenerative medicine. Applications should focus on the large-scale GMP grade production and manufacturing challenges associated with the use of EVs as therapeutics. Specific Objectives The goal for this funding opportunity is to support platform-oriented technology development associated with the production, manufacturing, and use, of EVs as therapeutics in regenerative medicine. Applications should focus on the large-scale GMP grade production and manufacturing challenges associated with the use of EVs as therapeutics. EV therapeutics would include, but are not limited to: 1) direct EV therapy (stem cell-isolated EVs produced under GLP conditions, and stored as off-the-shelf therapies); 2) designer EVs (personalized to the individual patient’s needs). Cell source can significantly influence the EV manufacturing process. Cell sources used for EV production should be well-characterized and reproducible to ensure consistency across preparations. GMP production grade EV products should be assessed and well-characterized for attributes such as purity (and the presence of contaminating factors), EV biophysical properties, and EV content, as critical quality control measures. Specific program objectives include: 1) The demonstrated ability to utilize stem cells such as mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs), or individual patient cells, to create EVs for specific and targeted tissue and organ repair. 2) The demonstration of GMP grade production of EVs for therapeutic applications. 3) The demonstration of the ability to repair and/or replace diseased organs for a specific human disorder relevant to regenerative medicine. Priority will be given to applications focusing on tissue/organ repair, and wound healing. 4) The validation of therapeutic benefits in vivo or ex vivo for the technology proposed. Phase I applications should include initial proof of concept studies focusing on feasibility and therapeutic applications in regenerative medicine. Phase II applications should optimize, refine, and scale-up technology platforms for the production and manufacturing of EVs using well-characterized cell sources and production-grade EV products. The validation of therapeutic benefits is required for phase II applications. This FOA will prioritize IND enabling therapeutic platforms that have the ability to work toward regulatory approval and commercialization. Regulatory engagement with the Office of Tissues and Advanced Therapies (OTAT) at the FDA Center for Biologics Evaluation and Research (CBER) is recommended, particularly for phase 2 applications. Applications should address the expected commercial impact of the proposed technology platform. Applications Not Responsive to this FOA The following types of studies are not responsive to this FOA. Applications proposing such studies will be considered non-responsive and will not be reviewed or considered for funding. - Projects are focused on the generation of liposome or other nanoparticle-based therapeutics. - Therapeutic applications outside the area of regenerative medicine. All applications must include project milestones as detailed in Section IV.2 - Application and Submission Information. Applicants are encouraged to contact staff at NCATS per Agency Contacts below to ensure that their aims and objectives are in line with the goals of the FOA.