HHS SBIR RFA-HL-15-030

Background

Stem cell-derived red blood cell (RBC) and platelet products have the potential to meet critical medical needs. Engineered RBCs might deliver drugs or biologic factors to treat diseases including inherited or acquired deficiencies. Blood cells derived from stem cells might be transfused into patients with sickle cell disease for whom compatible RBCs cannot be easily identified and stem cell-derived platelets might be transfused into patients at risk of developing platelet refractoriness. Many such patients could potentially benefit from personalized platelets or RBCs even if these products are more costly than the currently-available blood products. A few cell lines might be sufficient to cover most routine transfusion needs allowing for efficient RBC and platelet production and potentially longer storage shelf lives. Rare blood types might be selectively produced to ensure that patients in need will have compatible blood. Additionally, units could potentially be standardized and tested to provide well characterized pathogen-free cells in a standard minimum dose. The ability to produce blood products from expandable stem cells might begin to shift the blood supply dependency from volunteer donors to more predictable, renewable sources. For example, the blood supply might be maintained in times of national emergencies when blood centers may not be functioning or blood donors may not be readily available.

Work recently reported by various groups has demonstrated that such products can be developed from stem cells in sufficient quantity to be clinically relevant. What remains is to improve the process and to decrease costs. Specifically, remaining challenges exist in both the manufacturing process and additional discovery research. The manufacturing process needs to be made more efficient and cost-effective while assuring the effectiveness and safety of the blood products and enabling their commercial viability. Research to discover additional differentiation pathways that could be utilized in novel ways to efficiently produce clinically-useful stem cell-derived platelets or RBCs would be beneficial. For example, the final trigger for a megakaryocyte to begin elaborating proplatelets is not fully understood although numerous factors are known to affect and enhance this process. Further insight into these platelet-release factors may reveal new means to induce this process in culture. Additionally, while stem cell-derived red blood cells have been safety-tested in clinic, the efficacy of such cells remains to be tested. For stem cell-derived platelets, both safety and efficacy remain to be tested. Many of these areas require more basic or early translational research to advance our knowledge while others require improvement of the manufacturing process. RFA-HL-15-022 supports R01 grants to address the basic or early translational research needs whereas this Small Business Innovation Research (SBIR) Phase I and Phase II (R43/44) FOA along with the companion Small Business Technology Transfer Research (STTR) Phase I (R41) FOA (RFA-HL-15-029 ) supports small business awards to enable further advances in the manufacturing processes.

Purpose

This program aims to enable further advances in the manufacturing processes (tools and technologies) to take advantage of the existing knowledge and recent advances in the field to produce safe and functional red blood cell and platelet products at reduced cost.

Specific Areas of Research Interest

Research examples that would be considered appropriate include but are not limited to:

• Development of procedures, reagents or other technologies that enable efficient expansion of hematopoietic stem and progenitor cells at reduced cost for production of safe and functional blood products to allow clinical feasibility and acceptance:
• Development of small molecules and other new methods to bypass the need for expensive cytokines and animal feeders or sera
• Development of suspension culture systems for in vitro red blood cell production

• Development of techniques and tools for safety and efficacy assessment of stem cell-derived red blood cells and platelets for transfusion:
• Development of animal models for safety assessment.
• Development of potency assays to assess cell product efficacy.
• Development of technologies such as image techniques to track stem cell-derived red blood cells or platelets in vivo to assess whether these products transit, disperse and function as standard-of-care products do.

Applicants are strongly encouraged to discuss the proposed approach, concept, or strategy with Scientific/Research staff listed under Agency Contacts, to determine suitability to this FOA.

Note that this FOA is distinct from RFA-HL-15-004 , RFA-HL-15-008 , and RFA-HL-15-017 . The latter RFAs seek applications from small businesses to develop sophisticated and complex biomimetic culture systems that are capable of precise control of the cellular and 3-dimensional organ microenvironment, and which address the unique physiological dynamics of heart, lung and blood tissues.

Program Structure

A FOA that focuses on basic and translational research questions using an R01 mechanism to fund research project grants (RFA-HL-15-022 ) and two FOAs that focus on the research questions related to the required cell expansion and cell processing needed to produce GMP-grade products at clinical scale using the Phase I STTR (R41) and Phase I and II SBIR (R43/44) mechanisms (RFA-HL-15-029 and RFA-HL-15-030) form the combined program. This combined approach, with joint annual meetings between the basic research and small business investigators, is seen as vital to expediting the translation process. An annual grantees meeting will be held in Bethesda, MD. Where appropriate and possible, other interested stakeholders (e.g., industry and federal agency partners) will be included in joint meetings to promote the level of exchange and collaboration.

To be responsive to this FOA and the companion Phase I STTR FOA (RFA-HL-15-029 ), the proposed studies should demonstrate advances in manufacturing processes (tools and technologies) to produce safe and functional red blood cell and platelet products at clinical scale.