We aim to develop a novel stem cell treatment for spinal cord injury (SCI) that is substantially more potent than previous stem cell treatments. By combining grafts of neural stem cells with scaffolds placed in injury sites, we have been able to optimize graft survival and filling of the injury site. Grafted cells extend long distance connections with the injured spinal cord above and below the lesion, while the host spinal cord also sends inputs to the neural stem cell implants. As a result, new functional relays are formed across the lesion site. These result in substantially greater functional improvement than previously reported in animal studies of stem cell treatment. Work proposed in this grant will identify the optimal human neural stem cells for preclinical development. Furthermore, in an unprecedented step in spinal cord injury research, we will test this treatment in appropriate preclinical models of SCI to provide the greatest degree of validation for human translation. Successful findings could lead to clinical trials of the most potent neural stem cell approach to date.
Spinal cord injury (SCI) affects approximately 1.2 million people in the United States, and there are more than 11,000 new injuries per year. A large number of spinal cord injured individuals live in California, generating annual State costs in the billions of dollars. This research will examine a novel stem cell treatment for SCI that could result in functional improvement, greater independence and improved life styles for injured individuals. Results of animal testing of this approach to date demonstrate far greater functional benefits than previous stem cell therapies. We will generate neural stem cells from GMP-compatible human embryonic stem cells, then test them in the most clinically relevant animal models of SCI. These studies will be performed as a multi-center collaborative effort with several academic institutions throughout California. In addition, we will leverage expertise and resources currently in use for another CIRM-funded project for ALS, thereby conserving State resources. If successful, these studies will form the basis for clinical trials in a disease of great unmet medical need, spinal cord injury. Moreover, the development of this therapy would reduce costs for clinical care while bringing novel biomedical resources to the State.
The goal of this Development Candidate (DC) Award application is to identify a lead cell therapy candidate to treat acute spinal cord injury (SCI) and prepare that candidate to enter IND-enabling preclinical development by the end of the award period. The proposed DC consists of human neural stem cells (hNSCs) derived from human embryonic stem cells (hESC) suspended in a scaffold for injection into the injured spinal cord. In this proposal, the applicants intend to identify a lead cell line for clinical translation; validate the candidate and improve protocols using relevant preclinical animal models; develop scalable Good Manufacturing Practice (GMP)-compatible cell production methods; and perform preliminary safety studies to support the next stage of research.
Objective and Milestones
- The development candidate is scientifically reasonable and based on promising preliminary data.
- The plans to utilize preclinical animal models to demonstrate meaningful improvement in function, host-graft integration, and safety profile are logical.
- The milestones are sensible and, although ambitious, cover all the necessary elements to successfully lead into IND-enabling preclinical development and should be largely achievable within the proposed timeline.
- The timelines need clarification as it appears that certain studies are scheduled to start before the pilot material to be used in those studies becomes available.
Rationale and Significance
- Creating neural relays and capitalizing on the inherent plasticity of the spinal cord is a powerful concept that has long been recognized. If the applicants can demonstrate in relevant preclinical models findings similar to those described in the preliminary data, the significance would be great.
- The scientific rationale for using this approach is clear and compelling. The use of stem cell transplants for SCI thus far has been focused primarily on remyelinating damaged axons. In contrast, in the proposed studies, hNSCs have potential to act as a neural relay, which is an appealing concept.
- SCI remains an unmet clinical need despite active research in this area and the applicants support the potential for this approach to provide a substantial improvement over current therapies. Even an incremental benefit could substantially improve the quality of life and independence of SCI patients.
Research Project Feasibility and Design
- The investigators are to be congratulated for comprehensively addressing many of the right questions in their preliminary data and supporting further development of the candidate.
- In general, the research plan is well organized and logically presented, progressing through increasingly complex models towards clinical translation.
- The biologic effect of the cells in the preliminary data and the evidence that bridging axon growth underlies recovery of function is impressive. However, evidence of relays requires more detailed histologic and electrophysiological studies, and the applicant should more clearly indicate in data figures the source of cells.
- The proposed studies in the currently available preclinical animal injury models are warranted as the potential to demonstrate extensive process outgrowth in this model distinguishes this project from others in this indication. More importantly, reviewers considered that the ability to advance this candidate into the preclinical IND-enabling stage of clinical translation should hinge on this data.
- Despite the previous point, the applicants should consider moving to a more clinically relevant model (mentioned only in passing in the application) in future studies. The proposed preclinical injury model is not very clinically relevant and is unnecessary from a regulatory perspective, as a more clinically relevant injury model is likely to be required for dosing studies.
- The proposal lacks information on the use of immunosuppressive drugs in the preclinical model and does not properly justify dose. These studies are crucial as the immune suppression strategy is likely to be a major focus of clinical safety and the risk of life-threatening infections could outweigh the benefit of the therapy.
- Applicants intend that the single candidate cell line selected will be identified for future GMP production by the end of the grant period. However, sufficient information was not provided for reviewers to have confidence this will be achieved.
Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team
- The PI has an impressive track record and is particularly adept at leading preclinical findings to clinical translation. Also, the Co-PI has a notable track record with complementary expertise.
- The PI has assembled a strong team of experts who will provide supportive roles, particularly in development and evaluation of preclinical animal models.
- There is some concern that the PI and Co-PI are overcommitted and efforts on other projects may need to be reduced to accommodate this project.
- The team would benefit from a skilled electro-physiologist to work on the relevant preclinical animal model.
- Budget concerns include that funds are weighted towards salaries and subcontracts as opposed to actual experimental costs and the role of one contributor is uncertain, as experiments utilizing his expertise as described in his letter of support are not proposed in the research plan.
Collaborations, Assets, Resources and Environment
- All critical assets seem to be in place or in progress, although the possible need for licensing of propriety reagents was noted.
- The resources, environment and institutional support are excellent.
Responsiveness to the RFA
- Human stem cells are necessary to achieve the outcomes of the proposed research and a target for intervention has been identified.
- The approach is not especially novel, CIRM’s translational portfolio includes other SCI projects, and claims by the applicant that their preclinical models are unique are not supported by the literature. However, the comprehensive expertise brought to the project by involving experts in a wide variety of areas is novel and the prospect of accomplishing the neural relay formation in the preclinical models described in the application is compelling.