Disease Team Research I
Spinal cord injury is a devastating disease with no available treatments. It disproportionately affects young people who then lives many decades with the debilitation. In this project, we propose to develop a human neural stem cell line to treat spinal cord injury patients within 14 days after the injury. Administration of the cells into the injured tissue will limit the tissue from further damage and provide replacement neurons and glia that will promote self-repair and regeneration for the rest of the patient's life. During this project, we will assess the therapeutic as well as any toxicity potentials of the cells, using rats and pigs that will be injured in a manner similar to human spinal cord injury. These animal models will provide a rigorous testing grounds to prove or disprove potential clinical usefulness of the cells. If the cells can successfully treat rats or pigs with no major toxicity, then we will submit a IND application to the FDA to conduct a Phase 1 clinical trial with spinal cord injured patients.
Statement of Benefit to California:
The proposed research is to develop a stem cell therapy to treat spinal cord injury patients in the acute phase after the initial injury event. By intervening early, benefits of the stem cell transplantation to the patients are likely to be greatest. Thus, the patients in the trials will require intensive care and thus only the local population within California could participate. The treatment requires surgery and invasive injection of the cells into the injury site, which will require a special training. Thus, the benefit to the State of California is first access to this therapy for about 2-3 years before it becomes available elsewhere. Secondly, California has two federally funded Regional Spinal Cord Injury Care Centers that research various aspects of rehabilitation after spinal cord injury. Conducting clinical trials in California will become further catalysts to strengthen statewide treatment and rehabilitation centers for spinal cord injury patients.
The applicant proposes to use a human neural stem cell (hNSC) line for the treatment of acute spinal cord injury (SCI). The proposed studies are designed to provide proof-of-principle (POP) and non-clinical safety toxicology data in small and large pre-clinical animal models of contusion SCI. The hNSC line has been manufactured under current good manufacturing practices (cGMP) with a sufficient bank of clinical grade cell doses for clinical application, and an Investigational New Drug (IND) application for use of this cell line in Amyotrophic Lateral Sclerosis (ALS) is now under review by the FDA. Based on the studies performed for the ALS indication and studies in ischemic SCI models, the applicants expect that these cells can be injected intraspinally and will successfully engraft, fill the injured spinal cord cavity, and potentiate long-term neural plasticity and synapse formation. The proposed preclinical plan includes POP and safety studies that support the clinical objective to treat acute SCI within 14 days of injury by injection of the banked NSCs into the site of injury during the decompression surgery that is often performed to treat these patients. The POP studies will monitor clinically relevant improvements in rodent and porcine models of contusion SCI. The safety studies will evaluate multiple parameters including the injection protocol, the dosing scheme, and tumorgenicity. As the applicants propose to use allogeneic hNSCs without donor matching, an immunosuppressive (IS) regimen will be evaluated concomitantly with the proposed POP and safety studies. Reviewers considered the potential impact of a treatment for acute SCI to be significant and commented that the IND-enabling activities were complete and the timelines reasonable. However, the reviewers’ enthusiasm for this application was minimal due to the absence of preliminary data demonstrating POP in acute SCI and concerns regarding the clinical application of the proposed therapeutic. Reviewers agreed that a successful therapy aimed at the repair of the spinal cord would address a significant unmet medical need and would highly benefit patients suffering from SCI. Additionally, there is a strong rationale for the use of stem cell based therapies to restore function to SCI patients. Reviewers also concurred that this team could produce more than sufficient doses of clinical grade, GMP hNSCs and that the hNSC line has been demonstrated to have neuroprotective and neurorestorative effects in other indications. However, the reviewers were skeptical that the hNSC line could positively impact acute SCI patients, as the data presented to support the use of these cells in this indication was minimal. The lack of data in an acute SCI model was particularly problematic for reviewers since the rationale for the use of this hNSC line in acute SCI is based on a mechanism of action determined in ALS, a neurodegenerative disease; SCI occurs as a result of blunt trauma. However, one reviewer did note that cell-based therapies are likely to operate through multiple modalities and the same cell type could potentially be used to treat both indications despite their diverse pathogenicities. Reviewers were also disappointed by the lack of evidence demonstrating that the hNSC line provided any advantage over other cells that have been tested or are currently being tested to treat SCI. Robust evidence that this hNSC line is capable of synaptogenesis or circuitry restoration following engraftment and repopulation of the necrotic cavity would have increased the reviewers’ enthusiasm. Preliminary work has been done with the hNSC line in rodent and porcine models of SCI, and the preclinical development plan is complete with respect to IND required activities. However, reviewers noted the lack of preliminary data supporting POP in acute SCI and had concerns regarding the potential usefulness and potential consequences of the suggested clinical application of the hNSC line in acute SCI. Although reviewers praised the use of the porcine model of SCI as an improvement in modeling human injury, they were concerned that the low standard of improvement the applicant proposes to establish efficacy is unlikely to translate to a clinically relevant improvement or impact the standard of care for acute SCI patients. Furthermore, previously tested cell-based therapies can demonstrate similar levels of improvement so it is unlikely the hNSC line will provide a clinical advantage over other therapeutics previously proposed or in the pipeline. The reviewers’ concerns that the clinical application of the candidate hNSC line would be minimal were also impacted by the choice of acute SCI as the indication. They commented that it would be difficult to select appropriate patient candidates to receive this therapy and demonstrate clinical efficacy, since acute SCI is extremely variable and clinical assessments during the acute phase are often inaccurate and outcomes are difficult to predict. Additionally, the cells would be injected into the spinal cord during the decompression surgery that is currently used to treat many acute SCI patients. This type of surgery itself provides a significant benefit and reviewers felt that it will be difficult to assess the additional benefit of the cell therapy. The applicant did not address either of these issues. Reviewers were additionally concerned by several safety considerations that were either not addressed or were minimally addressed in the proposal. The applicant is proposing to inject allogeneic cells into the necrotic cavity during decompression surgery following a contusion SCI. These cells will engraft and fill the cavity. While the applicant considers this important to providing a therapeutic benefit, the reviewers were not convinced. The potential for the cells to form a mass that would compress and compromise the injured spinal cord further complicates the issue of benefit in acute SCI patients. Although the applicant does propose to monitor the animal models and patients for growth of a mass, it is not clear how this adverse event would be monitored in animal models or managed clinically should it occur. Reviewers also noted the lack of attention given to the potential independent effects of the IS regimen on the SCI, the potential for development of neuropathic pain syndromes following cell injections, and the proposed cell delivery approach. The applicants do propose to monitor the toxicity of the IS regimen, but they do not consider how it will alter the spinal cord injury response. Moreover, reviewers noted that the proposed IS regimen seemed excessive given that the cell delivery site (central nervous system) is a relatively immune privileged site. Several studies have demonstrated that multiple cell types can cause neuropathic pain when injected into the spinal cord. The applicants do not address this issue, and, since data on the composition, purity, and antigenic characteristics of the transplanted cells are not provided, the reviewers could not evaluate the potential for neuropathic pain following injection of the hNSCs. Finally, the applicants paid little attention to selecting an injection paradigm to deliver the cells to the site of injury. This omission concerned the reviewers not only because it is far from clear which mode of delivery yields the best outcomes, but also because given the quality of the experts on this team, this deficiency suggests the quality of communication between the collaborators is not adequate. The quality of the primary investigator (PI) and the research team was considered one of the strengths of the proposal. Reviewers acknowledged the percent effort of the PI and appreciated the considerable regulatory experience the PI brings to the team. The collaborators provide a strong background in the study of cell therapies for SCI and extensive experience in treatment of SCI. Reviewers noted the connection between the PI, the co-PIs, and the neurosurgical team and were particularly pleased that proposed porcine surgical team is the same clinical team that would be likely to perform the surgical procedure in human should a clinical trial result. There was concern that the governance structure was undefined, conflict resolution mechanisms were not proposed, a project manager had not yet been identified, and a large portion of the experimental work would be subcontracted. However, the facilities are in place and provide all the appropriate resources to complete the proposed research. Overall, while reviewers recognized the significant need for treatment options and the appropriateness of a cell-based therapy for the treatment of acute SCI, the use of this hNSC line in acute SCI was not supported by proof-of-principle or safety data. Furthermore, while reviewers noted that the proposed plan is likely to support an IND for the hNSC line, they were concerned that the proposed therapeutic was not translatable to the clinic and would not provide a clinical benefit to the patient population.
- Darin Weber