Funding opportunities

Development of pluripotent-derived hNSC candidate cells for the treatment of chronic SCI

Funding Type: 
Early Translational III
Grant Number: 
TR3-05575
Funds requested: 
$5 230 535
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
Multipotent human neural stem cells (hNSC) have shown potential for the treatment of disease and injury in the brain and spinal cord. hNSC can be derived from adult or fetal tissue, as well as from pluripotent cells. Cells have surface markers that can be selected for or against by cell sorting techniques. Selecting fetal hNSC for the cell surface marker CD133, and against the cell surface marker CD34, enriches for cells that can survive, migrate, and repair the injured spinal cord. Experiments testing fetal hNSC selected for these markers have led to several clinical trials in the USA, as well as a trial for chronic spinal cord injury approved in Switzerland and ongoing at the University of Zurich. In addition, selection for these markers may reduce the potential for tumor formation by pluripotent-derived hNSC. As banks of pluripotent human embryonic stem cells are developed for to allow donor-host immunological matching, and the technologies for individual patient-derived human induced pluripotent cell therapies are realized, strategies to enhance safety and consistency, such as selecting for cell surface markers, may enable translation of these pluripotent cells. However, sorting human pluripotent stem cells for these cell surface markers has not been tested. In this proposal, we seek to develop clinically compliant GMP grade pluripotent-derived hNSC selected for these surface markers, and test their efficacy and safety in the treatment of chronic spinal cord injury.
Statement of Benefit to California: 
Multipotent human neural stem cells (hNSC) have shown potential for the treatment of disease and injury in the brain and spinal cord. hNSC can be derived from adult or fetal tissue, as well as from pluripotent cells. Cells have surface markers that can be selected for or against by cell sorting techniques. Selecting fetal hNSC for the cell surface marker CD133, and against the cell surface marker CD34, enriches for cells that can survive, migrate, and repair the injured spinal cord. Experiments testing fetal hNSC selected for these markers have led to several clinical trials in the USA, as well as a trial for chronic spinal cord injury approved in Switzerland and ongoing at the University of Zurich. In addition, selection for these markers may reduce the potential for tumor formation by pluripotent-derived hNSC. As banks of pluripotent human embryonic stem cells are developed for to allow donor-host immunological matching, and the technologies for individual patient-derived human induced pluripotent cell therapies are realized, strategies to enhance safety and consistency, such as selecting for cell surface markers, may enable translation of these pluripotent cells. However, sorting human pluripotent stem cells for these cell surface markers has not been tested. In this proposal, we seek to develop clinically compliant GMP grade pluripotent-derived hNSC selected for these surface markers, and test their efficacy and safety in the treatment of chronic spinal cord injury.
Review Summary: 
This application for a Development Candidate (DC) Award focuses on a human embryonic stem cell derived neural stem cell (hES-NSC) therapy for chronic traumatic spinal cord injury (SCI). The DC will consist of a sorted subpopulation of hES-NSC that is expected to retain multipotency while presenting a reduced risk of tumorigenesis compared to the starting population. Four aims have been proposed to advance this objective: 1) To develop stable CD133+/CD34- hES-NSC candidate lines from two different Good Manufacturing Practices (GMP) -compliant hES starter populations under xeno free conditions; 2) Demonstrate the ability of CD133+/CD34- hES-NSC to improve recovery of function in a chronic thoracic SCI model; 3) Evaluate the safety and tumorigenicity of these cells in an immunodeficient SCI model; and 4) Obtain evidence for therapeutic method of action (MOA). Objective and Milestones - The proposed approach represents a logical extension of current knowledge and established precedent, but there is no clear hypothesis presented as to what is expected of the cells. Instead, a broad examination of “disease modifying activity” and “method of action” are described, leaving reviewers with the impression that the proposal is more about “seeing what happens” than addressing specific phenomena. - Milestones are well articulated and represent achievable goals within the given time frames. Outcome measures and decision points are clearly stated. Rationale and Significance - The proposed DC targets a significant unmet medical need, as there are limited therapeutic options for sufferers of chronic SCI beyond physical therapy. - There is good rationale for exploiting a readily available and expandable cell source (hES) to derive CD133+/CD34- NSC populations, whose fetal-derived counterparts have shown promise for clinical use but are limited in availability. Research Project Feasibility and Design - The preliminary data did not convince reviewers that the proposed therapeutic population would prove any more effective in enhancing locomotor recovery than control cells or cell types that have been previously examined. The lack of data showing behavioral outcomes was also disconcerting. - It is not clear that the proposed in vitro studies would yield information that is relevant to what occurs in vivo. - Convincing data were provided to suggest that CD133+/CD34- NSC with favorable properties similar to those derived from other tissues can be obtained from hES sources. - The research plan is straightforward and feasible but would benefit from additional discussion around experimental parameters such as injury location and severity, timing of transplant, and how certain data, such as the sensory pain assessments, would impact go/no go decisions. - Reviewers suggested that the applicant restructure the research plan and milestones to first demonstrate whether there is any increased efficacy of the proposed cell population compared to other grafted cells, and this need not be done with GMP isolated populations and housing conditions. Only if initial efficacy can be convincingly established should the remainder of project goals be undertaken. Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team - The PI is a highly accomplished investigator in the field of stem cells and SCI, with considerable relevant experience in translational research. Reviewers were somewhat concerned, however, that the level of commitment proposed would be difficult to achieve given the number of additional active and pending awards. - The research team comprises all of the necessary expertise to successfully conduct the proposed studies. - Reviewers found the budget as a whole to be inflated, and there was insufficient justification provided to account for the notably high histology and cell culture costs. Collaborations, Assets, Resources and Environment - The resources and environment in which the proposed work will be conducted are excellent. There is clear evidence of institutional support. - Resources available to the team through collaborators are satisfactory, although a letter of support from the GMP line supplier was not included. Responsiveness to the RFA No relevant concerns were highlighted by reviewers under this review criterion.
Conflicts: 

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