Funding opportunities

Human pluripotent stem cell based therapy of blood disorders

Funding Type: 
Early Translational IV
Grant Number: 
Funds requested: 
$5 397 001
Funding Recommendations: 
Not recommended
Grant approved: 
Public Abstract: 
Recent technical advancements in human embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) production have revolutionized their potential applications in regenerative medicine. However, a remaining hurdle in this process is the need for efficient, effective, and stable generation of specific cell types from such stem cells for therapeutic use. The ultimate goal of the proposed study is to develop a novel cell therapy approach to increase the production of therapeutically useful blood cells from human PSCs, especially from patient-specific and genetic mutation corrected iPSCs. Currently, bone marrow transplantation is the best way to cure many blood-related disorders, such as sickle cell anemia, thalassemia, aplastic anemia and certain leukemias. Furthermore, blood transfusion is an effective way to rapidly counteract blood cell loss due to ablative treatments, such as chemotherapy and radiation therapy. Unfortunately, the limiting factor in transplantation and transfusion treatments is the lack of matched donors. The ability to produce unlimited numbers of blood stem cells and/or functioning differentiated blood cells from human ESCs and patient-derived iPSCs will greatly improve availability of such treatments. In this application, we propose to develop stem cell therapies that enhance production of functional blood cells from human iPSCs via delivering cell membrane penetrating factors in cell culture medium. This is highly relevant to the main goals of CIRM.
Statement of Benefit to California: 
Thousands of Californians are suffering from blood-related diseases that may potentially be cured with bone marrow transplantation and/or blood transfusion. However, these life-saving measures are limited by a lack of eligible donors and the necessity of finding correctly matched blood products. Current treatments for some of these conditions can cost patients tens of thousands of dollars per year. Despite these treatments, many patients die from their disease waiting for a bone marrow transplant. Recent technical advancements in human pluripotent stem cells (PSCs) have revolutionized their potential applications in regenerative medicine and have provided enormous hope for these patients. We propose to develop a novel approach to enhance the specificity and efficiency in the production of therapeutically useful blood cells from human PSCs. Therefore, one long term benefit of the proposed work is to improve the treatment of thousands of Californian patients who need to receive healthy, functioning blood cells to alleviate their disease conditions. In turn, this will benefit California’s financial status in reducing the cost of treating these patients with expensive yet ineffective methods. Furthermore, the proposed research will continue to maintain California’s leadership in the field of stem cell research to provide training and education of some of California’s bright young minds.
Review Summary: 
The objective of this Development Candidate (DC) award proposal is to develop a novel approach for making blood stem and progenitor cells (HSCs) from human pluripotent stem cells (hPSCs). The approach will use a highly purified, cell penetrating, biologically functional and GMP grade transcription factor to enhance efficiency and specificity of HSC derivation. The investigator intends to optimize production of the cell penetrant transcription factor, evaluate its activity in combination with other factors known to enhance hematopoiesis and elucidate the molecular mechanisms involved in the transcription factor-induced HSC differentiation. Objective and Milestones - The objective of this proposal is not sufficiently focused on developing a therapeutic candidate - The TPP was not considered appropriate as the production of the proposed transcription factor would be considered an “ancillary reagent” (used for cell production) rather than a therapeutic candidate that would be administered to patients. - The milestones are appropriate for the given research plan, but did not elaborate or adequately provide defined success criteria or firm “go/no go” parameters to guide evaluation of a development candidate. Rationale and Significance - While the need for improved methods for producing patient-compatible HSCs is significant, reviewers were not convinced that the proposed transcription factor or transcription factor-treated cells would be the optimal approach or that it would be an improvement over previous approaches. - The project was not considered particularly novel, as other reports have described approaches similar to that proposed. - The proposed project, even if successful, was not judged to be “transformative”. Although the goal is to obtain hematopoietic differentiation and expansion with the transcription factor, the proposal does not focus on development of a HSC cell transplant development candidate for a defined clinical indication. Feasibility and Design - Preliminary data were considered strong. However, these data were not used to design a research plan for a development candidate. - The research plan for the production and optimization of the transcription factor production are clearly laid out, but the applicant did not propose a plan for a well-characterized HSC therapeutic development candidate. - There was concern that in vivo experiments were not adequately described, and the timing of these experiments (late in the project period) was considered problematic. Consequently, the reviewers felt that the project will not be ready to enter IND-enabling stage of research at the end of the award period. - The research plan was focused on basic biological study rather than on pre-clinical research, and the applicant failed to narrow the disease indications for a Phase 1 clinical trial from the general category of human blood disorders. Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team - The PI and research team were considered strong and had the expertise and background to perform the proposed work. Collaborations, Assets, Resources and Environment - The Collaborators, resources and environment were considered strengths. Responsiveness to the RFA - The application was not found to be responsive to the RFA as a DC award, since the focus of the proposed research was primarily basic research study rather than directly pre-clinical or translational.

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