Executive Summary This applicant proposes to develop a team to support the transplantation of embryonic stem cell-derived oligodendrocyte precursor cells into patients with spinal cord injury (SCI) to promote remyelination. Spinal cord injury remains a major unmet clinical need, and interventions to promote functional recovery in the damaged spinal cord are required. Reviewers noted that SCI represents a highly accessible and clinically important target for stem cell medicine. In fact, Geron is pursuing the proposed therapeutic concept and hopes to enter the clinic this year. Reviewers agreed that this was a very interesting application. They commented on the quality of the investigator’s research, and pointed out that the PI has thought seriously about translation: his/her lab has developed technologies to differentiate ES cells into oligodendrocyte progenitors, and has addressed issues of regulation and clinical use. The PI is a well established, internationally recognized leader in the field of SCI and of neurorestorative approaches to improving spinal cord function. S/he has extensive experience in cell based therapy in preclinical models of SCI. In addition, the applicant’s laboratory has made considerable investments in the regulatory issues regarding the generation of such transplantable cells. It is very much to the applicant’s credit that s/he addressed the regulatory issues surrounding cell implantation therapies. Furthermore, the lab contains a quality assurance unit, which is good evidence that the PI has considered the translational issues very carefully. There was evidence by the PI of particular thought to the planning process, with four different sources of advice being sought, although the reviewers would have liked a better indication of who are some of the team members under consideration. Reviewers raised two major concerns with the application. The reviewers raised the question of the rationale for conducting these studies in light of a proposed clinical study using the same cells. Although the applicant argues that more research will be needed in areas including methodology, immunosuppression, biomarkers, surgical delivery, outcome measures, rehabilitation and combination treatments; reviewers were not convinced that a separate program is required. Reviewers also had significant concerns about the therapeutic concept. The PI argues that, in addition to the axonal damage, demyelination is a prominent feature following spinal cord injury and contributes to the impairment. One reviewer pointed out that a much smaller body of literature supports the concept of demyelination contributing to disability compared to that of axonal degeneration. A number of studies have shown that remyelination improves axon conduction and protects axons, and a single study is cited showing that transplanted oligodendrocyte precursor cells improve function following incomplete spinal cord injury in rats. Three subsequent studies are cited that apparently support this conclusion but unfortunately are not included in the bibliography. Only one of these studies seeks to argue directly that the myelinogenic capacity of the transplants might contribute to repair. An important implication of this as noted by one reviewer is that the potential differential contributions to clinical recovery from remyelination versus axon regeneration may present analytical challenges during preclinical and clinical studies. Should the degree of clinical recovery be small, as is likely based on early proof of concept studies, it might be difficult to distinguish effects attributable directly to remyelination from those attributable to any neuro-protective or axon-regenerative effect of the transplanted progenitor cell population. Reviewers commented that current imaging techniques would be poor at assessing remyelination, and biopsies of the lesion site would be impossible. Thus, reviewers could not grasp how the differential contribution of remyelination could be measured. In summary, reviewers judged that the rationale for this disease team approach was not strongly supported. Reviewer Synopsis This project targets spinal cord injury. The case is made convincingly that this is a significant and important medical issue, with the ever longer life expectancy of patients with spinal cord injury resulting in significant individual, societal and economic burdens. The authors argue that demyelination is a prominent feature following spinal cord injury in addition to the axonal damage and contributes to the impairment. The project cites a number of studies showing that remyelination improves axon conduction and protects axons. A single study is cited to show that transplanted oligodendrocyte precursor cells improve function following spinal cord injury in rats. Three subsequent studies apparently support this conclusion (but unfortunately are not included in the bibliography). However, only one of these seeks to argue directly that the myelinogenic capacity of the transplants might contribute to repair. Reviewer One Comments Concept: This proposal focuses on cell therapy for the treatment of spinal cord injury. Spinal cord injury still remains a major unmet clinical need and interventions to promote functional recovery in the damaged spinal cord are still required. It is still uncertain, however, the extent to which cell based therapy for spinal cord injury may prove to be of therapeutic value. Nevertheless the P.I. of this proposed team has extensive experience in cell based therapy in preclinical models of spinal cord injury in which significant functional improvement has been seen. These studies form the basis for a proposed clinical trial using human ES cell derived oligodendrocytes to be initiated later this year pending FDA approval. Principal Investigator: The PI is a well established internationally recognized leader in the field of spinal cord injury and neurorestorative approaches to improving spinal cord function. However, with the exception of the inclusion of Lauren Black, an FDA cell therapy expert, there is no mention of who the PI intends to recruit into this team. (The panel was reminded that a fully-formed and named team was not a requirement of this RFA). Planning Approach: As a proposed disease team planning proposal this proposal is not appropriate as, with the exception of an ex-FDA official, there is no mention of the personnel that the PI intends to recruit into this disease team. (The panel was reminded that a fully-formed and named team was not a requirement of this RFA). Reviewer Two Comments Concept: The proposal here is to transplant ES cell-derived oligodendrocyte precursor cells into patients with spinal cord injury. The applicant’s laboratory has made considerable investments in the logistic and legal issues regarding the generation of such transplantable cells and has FDA-compliant human ES cell-derived oligodendrocyte precursors already available. Of note, however, Geron is planning a phase I clinical trial in spinal cord injury with these cells in 2008 but the applicant argues that more research will be needed in areas including methodology, immunosuppression, biomarkers, surgical delivery, outcome measures, rehabilitation and combination treatments. For this reason, he argues that a separate and more detailed clinical trial is required. Plausibility of target Spinal cord injury represents a highly accessible and clinically important target for stem cell medicine. Decades of prior research into the response to injury and regeneration in small animal and primate models makes this a highly studied system. A number of alternative methods to promote regeneration (addressing the problem of axonal regeneration rather than remyelination) are in pre-clinical or clinical trials, making the potential for developing combination therapies excellent. Together, these make the injured spinal cord an optimal target for stem cell medicine. Evidence in support of therapeutic concept The vast majority of research into regeneration of the spinal cord has focused on axonal regeneration and the role of intrinsic and extrinsic inhibitory factors that prevent efficient regrowth of severed axons. The applicant has argued that the demyelination also known to occur distal to spinal cord injury represents an important cause of disability and one that is amenable to transplantation-based strategies that have been well validated in the genetic models of demyelinating disease. This conclusion is supported by his own work and one of the other studies cited. However, it is important to realize that there is a much smaller body of literature here and that the potential contributions to clinical recovery that would be made by efficient remyelination and efficient axon regeneration are likely to be rather different. This may become an issue in the analysis of the clinical studies. Given that it would be impossible to biopsy the lesion site to assess the efficacy of the transplantation, MRI is likely to be the method of choice for assessing remyelination. However, MRI is poor at assessing remyelination. It follows that, should the degree of clinical recovery be small as is likely in early proof of concept studies, that it might be difficult to distinguish effects attributable directly to remyelination from those attributable to any neuroprotective or axon-regenerative effect of the transplanted stem and precursor cell population. Thus, I think there must be significant concerns over the therapeutic concept here. Can it go to clinic in 5 years? Clearly yes, as these cells are due to go into the clinic next year in the Geron trial. Importance of problem and ability to advance stem cell medicine to the clinic As I have argued above, the feasibility of this study is high but analysis of the outcome might be complex and certainly needs further consideration. Principal Investigator: Track record of Principal Investigator The applicant has an excellent track record and has been one of the pioneers in the development of ES cell-based cell populations for therapy. His energy and enthusiasm is reflected by his significant ability to attract funds for his translational research programmes. Translational expertise of Principal Investigator It is very much to his credit that the applicant has addressed the regulatory and legal issues surrounding cell implantation therapies. His lab contains a quality assurance unit, which is good evidence that he has considered the translational issues very carefully. Leadership qualities of Principal Investigator As evidenced by his ability to attract collaborators, industrial partners and funding, leadership potential is good. Planning Approach: Merit of planning process proposed; is it well thought out? I thought there was evidence of particular thought to the planning process, with four different sources of advice being sought. The focus groups I thought an excellent idea and they do address many of the key issues. How good is the team? It is not clear from the application exactly who the team members will be. We are only told that it will include investigators from UCSF, Stanford, UCLA, UCI and UCSD. These institutions clearly contain internationally-leading stem cell biologists and physicians, but evidence of those who are prepared to participate would have been helpful. Will an award enable the team to prepare a competitive application? The feasibility of this project and the skills of the applicant will certainly enable the planning process to deliver a competitive application. An issue that would need to be addressed in some detail is the relation of the proposed trial with that planned by Geron using exactly the same cell population. It would need to be very clear that the two trials were sufficiently distinct to merit both going on at the same time.