Disease Team Research I
Spinal cord injury is a particularly debilitating form of trauma, in part because there is no current curative treatment. The unmet medical need in patients who have suffered paraplegia or quadriplegia has long been recognized as one that is in need of novel therapeutic approaches. Stem cell-based strategies may offer a broad regenerative platform that may address many aspects of the injury to the spinal cord and create opportunities to intervene long after the initial trauma. Spinal cord injury (SCI) affects a variety of neural cells, such as neurons and oligodendrocytes. The latter produce myelin, an insulating sheath that ensures normal conductivity. Therefore, an approach that offers the replacement and/or restoration of function to damaged cells holds much promise. Research has now shown that cell therapy may be capable of producing more than one effect in the injured spinal cord. The spectrum of benefits derived from this approach explains why this area is now a major research focus not only for SCI, but other neurological diseases as well. Research with central nervous system stem cells derived from the human brain have demonstrated that these cells survive after transplantation, differentiate into neurons and oligodendrocytes, and most importantly improve neurological function in animal models of SCI. One of the first steps prior to testing a potential therapy in humans is to conduct animal experiments in models that reflect the human trauma as closely as possible. Therefore the primary goal of this research is to establish further evidence that the human central nervous system stem cell (HuCNS-SC) is safe when transplanted into the spinal cord, and that it also leads to a better recovery when compared to animals that did not receive transplantation. The research proposed will study the effects of HuCNS-SC cells in the setting of lower SCI (thoracic cord trauma that results in paraplegia) and upper SCI (cervical cord trauma that leads to quadriplegia) in animal models that will allow survival of the human cells. Effectiveness will be tested by measuring neurological function and determining the degree of improvement after transplantation of the human cells. Safety will be tested by closely examining the animals to show that there are no adverse reactions to the transplanted cells. Investigating the effects of human central nervous system stem cells in these animal experiments will enable collection of data necessary to begin human clinical trials. The regenerative therapy potential represented by stem cells for patients with spinal cord injury has captured the imagination of scientists and patients alike. The opportunity to embark on this exciting field of research shows that new approaches are on the horizon and the field of cell therapy for spinal cord injury will be significantly advanced by the results obtained in this research program.
Statement of Benefit to California:
Spinal cord injury (SCI) causes a devastating condition; its effects vary depending on the level and degree of damage to the spinal cord. The trauma usually occurs at younger ages and results in a lifetime of paralysis which becomes associated with other medical complications and creates significant demands on the health care system. SCI is the second leading cause of paralysis in the US and it is currently estimated that there are approximately 1.3 million affected individuals. Although there are no official estimates, it is projected that there are more than 140,000 Californians living with SCI. In addition to the considerable personal burden placed on the individual and family, the economic impact of SCI is highly significant. The estimated costs related to loss of wages and health care for affected patients may be higher than 1.5 billion dollars annually for patients living in California. A therapy that can restore at least some spinal cord function has the potential for a significant improvement not only in the patient’s quality-of-life, but also the shared costs of health care and loss of productive employment. The use of stem cells, and in particular human central nervous system stem cells (HuCNS-SC) , as therapeutics for SCI holds much promise for ailing patients. Most clinical investigations for SCI have focused on developing treatments that are aimed at very early time points after injury and have not been associated with major changes in outcome. This research will focus on developing an approach that will have broader applicability in terms of larger window of treatment after injury and include both upper and lower levels of spinal cord trauma. The development of a novel treatment that can address time points beyond the acute phase of trauma, and include thoracic as well as cervical levels, will more fully address the unmet medical need of the entire spectrum of patients with SCI. The range of potential benefit to patients includes improved sensory, motor, bowel/bladder, and even important reflex, or autonomic, function. A change in any one or combination of these deficits, if only for one or two spinal cord functional levels, could translate into improved quality-of-life for a patient. The results of the research proposed will enable the regulatory approval and execution of clinical trials using hCNS-SCns to treat spinal cord injured patients. This research program will capitalize on the combination of a team of world-class scientists and clinicians in California that together can advance this field of endeavor. The outcome of the proposed studies will help not only those Californians with SCI, but will more globally pave the way for the use of stem cells in a variety of diseases. Additionally, our California-based effort will not only help individuals ailed by this state, but will also ensure that California ranks very highly in terms of SCI therapeutic advances and benefits from jobs created and retained.
This proposal plans to develop human central nervous system stem cells (hCNS-SCs) to treat sub-acute to chronic spinal cord injury (SCI). hCNS-SC can differentiate into oligodendrocytes, astrocytes and neurons. The applicant proposes to transplant hCNS-SCs to injured spinal cords where they will differentiate into oligodendrocytes and re-myelinate axons spared by the spinal cord injury, promote their survival, and thereby restore neurological function. The team plans to perform preclinical studies to permit the filling of INDs for the treatment of both thoracic and cervical SCI within four years. The applicant has established methods for the generation of clinical grade hCNS-SC; therefore, the preclinical development plan will focus on IND enabling safety and efficacy studies following hCNS-SC transplantation. The bulk of these studies will use immunologically-compromised rodent spinal cord injury models. The first series of experiments will address thoracic injuries. Long-term safety studies will evaluate histopathology in CNS and peripheral organs including tumor or cyst formation, tissue disruption and grafted cell fate up to nine months. Pharmacology/toxicology studies seek to determine behavioral improvements from the therapy at various times post injury and will also check for allodynia, an abnormal pain response to a non-painful stimulus. Following the refinement of the cervical injury model and development of outcome measures, a similar series of pharmacology and toxicology studies will be performed in a cervical injury model. To prepare for entry into the clinic, the team will also develop cell delivery techniques in a relevant, immunocompetent spinal cord injury animal model. Spinal cord injuries result in devastating loss of function and quality of life. For acute injuries, early interventions have only limited success, while for chronic injuries; there are no effective treatments. If successful, the proposed treatment could have great impact and fill an unmet medical need. Reviewers also felt hCNS-SC to be an appropriate therapeutic cell type for SCI. However, they questioned the underlying rationale that reversing demyelination will be sufficient to improve function in humans. Additionally, they felt that the applicant had not adequately considered the impact of other factors that inhibit SCI recovery such as glial scarring and soluble inhibitory factors. Reviewers appreciated the well-written proposal, its logical plan and the detailed description of most experiments. The ability to make clinical grade hCNS-SC and the teams’ successful IND experience with these cells enhance feasibility of the proposed program. However, reviewers noted significant weaknesses in the feasibility based on both insufficient preliminary data and deficiencies of the selected in vivo models. In particular, the preliminary data do not demonstrate a correlation between engraftment and efficacy. Furthermore, preliminary results revealed no statistically significant difference in the benefits derived from hCNS-SC as compared to fibroblasts in the in vivo SCI model. Reviewers suggested that a head to head comparison of autologous fibroblasts and hCNS-SC, confirmation that hCNS-SC would, indeed, myelinate demyelinated axons and more convincing efficacy data would strengthen the proposal. Reviewers also expressed concerns about the selected outcome measurements and a number of additional aspects of the project’s feasibility. In particular, they considered the open field locomotor test to be insufficient as a functional measure and suggested that the applicant require efficacy in more demanding, species-appropriate, volition based functional tests. From a safety perspective, concern was expressed that re-myelinated neurons could produce aberrant transmission and result in development of serious pain syndromes. Reviewers felt that the immunocompetent preclinical model studies were inadequately addressed, and plans to extrapolate from immunodeficient models were insufficiently described. Description of the surgical cell delivery technique, a critical component for translating the program to the clinic, was lacking. Reviewers also found that contingency plans for problems that may arise were lacking, and this and other omissions led reviewers to question whether the applicant had sufficient experience to lead the translational effort. Lastly, milestones and go/no-go decision points did not provide adequate quantitative success measurements. Reviewers praised the PI’s extensive publication record in the SCI field and expertise in SCI models and cell therapy. The team provided further SCI and stem cell therapy expertise. However, the PIs apparent lack of experience with the immunocompetent SCI model left reviewers uncertain whether the PI could supervise the entire program. The team would benefit from the inclusion of a clinical neurosurgeon with neurotrauma and clinical trial expertise, a transplant surgeon familiar with immunosuppression and a clinical neurologist. The available resources and environment are excellent, as is the external advisory board. In summary, this is a proposal to use neural stem cells to treat spinal cord injuries. Strengths of the proposal include its focus on a significant medical need, the ability to produce clinical grade hCNS-SC, and an experienced research team. Major weaknesses include serious concerns about the project’s feasibility and overall maturity. These factors led reviewers not to recommend this program for funding.