Early Translational III
Traumatic brain injury (TBI) is a global epidemic leading to poor outcome in 50% of mostly young individuals. Yearly in the US, 1.7 million TBIs occur; in [REDACTED] TBI causes 235/100,000 hospital admissions. The financial burden is estimated over $60 billion/year in the US and $8.6 billion/year in [REDACTED]. Diffuse TBI affects up to 70% patients with head injury, causing progressive axonal degeneration, myelin degradation and permanent deficit. Currently, there are no effective treatments to halt delayed brain damage and neural stem cell therapies offer great potential. The partnership of 2 successful neurotrauma groups in CA and [REDACTED] aims to establish a novel stem cell transplantation therapy in a well characterized diffuse axonal injury model. Importantly, diffuse axonal injury is a significantly different target than the focal contusion model of TBI currently in CIRMs portfolio. Clinical grade human neural stem cells, neuronal restricted progenitors (NRP) and/or glial restricted progenitors (GRP) derived from ES cells will be transplanted into injured brain; concurrent infusion of LIF is expected to enhance survival of transplanted cells, promote axonal repair and remyelination. Validated neurological measures will be used to determine therapeutic efficacy, including tests similar to those conducted in humans, such as diffusion tensor MRI imaging to measure tissue damage. This study will delineate a new cell therapy paradigm for the treatment of patients with diffuse TBI.
Statement of Benefit to California:
This project has the potential to develop a new therapeutic paradigm for the treatment of patients with traumatic brain injuries. TBI has been called a silent epidemic, affecting more people than breast, lung, prostate, brain, and colon cancer combined. Currently no therapies can reverse the detrimental effects of brain injury, leaving mostly young patients with permanent disabilities. Our goal of specifically targeting diffuse brain injury (the most abundant form in humans), has critical implications for the benefit of this large patient population globally. This study sees the partnership of two eminent neurotrauma groups in CA and [REDACTED] that merge decades of experience in neurotrauma research and expertise bring stem cell therapies to trial. The established collaborations of these PIs with local specialists consolidate an interdisciplinary approach adding huge credentials to this study. In [REDACTED], the proximity of the team with a major trauma centre where specialist clinicians have years of experience in conducting clinical trials on head trauma patients, sees an authentic opportunity for the future translation of a revolutionary cell based therapy in patients with brain trauma. At 12% of the US population, over 200,000 California’s per year are projected to suffer a TBI; with an economic cost to the state of well over 7 billion dollars annually. Even a small improvement in outcome would benefit patients, their families and the economic position of CA and [REDACTED].
This is a Development Candidate (DC) proposal which seeks to develop transplantable human embryonic stem cell (hES)-derived neural stem cell (hNSC) or neural / glial restricted progenitors and utilized for repair in a diffuse axonal injury model of traumatic brain injury (TBI). The applicant has established two xenofree clinical grade hNSCs that will be sorted to isolate neural restricted precursors and glial restricted progenitors, resulting in total of 6 lines. The best two of these lines will be selected based on several criteria including differentiation capability, myelination potential, graft survival, and will be transplanted into a diffuse axonal injury model of TBI and assessed for disease modifying activity. Objective and Milestones - Reviewers argued that since the progression of the injury is mainly due to diffuse axonal injury and disconnection, it is difficult to envision how cell replacement therapy would serve to restore meaningful axonal reconnectivity. They further agreed that given the progression of diffuse axonal injury is progressive and prolonged; multiple treatment interventions may be necessary. - Reviewers also questioned the feasibility of an early and invasive surgical transplantation procedure (7 days post-TBI), as it is likely to be considered extremely risky to produce further surgical trauma during the early post-brain injury period. - Reviewers agreed that the milestones need to be significantly more concise with a distinct outcome measure of at least a 25% improvement. The multiple and diffuse nature of the milestones further dampened reviewers’ enthusiasm. Rationale and Significance - Reviewers found the proposal at the exploratory stage and further argued that since the critical deficits and targets for repair are not understood, the rationale for developing hES-derived cell replacement therapy for this purpose is poorly developed. They raised further concern that due to the nature of chronic and progressive axonal loss in this pathology, the treatment window will be extensive. - Reviewers advised that rather than attempting to replace neural populations, a treatment to prevent progressive degeneration by rescuing damaged cells and axons may be more feasible. - Although reviewers agreed that development of a strong preclinical model with predictive validity and testable pathology is an unmet need and essential in order to identify promising therapies for TBI, they found that achieving a development candidate ready for IND-enabling work in 3 years is unlikely. Research Project Feasibility and Design - Given the significance of cognitive function following TBI, reviewers were unclear on the outcome measures and interpretations of the proposed cognitive tests in the model used. They found the proposal lacking sufficient details on behavioral outcome measures and transplant effects. - Since there were numerous possibilities for selection criteria, reviewers found it difficult to envision how the optimal candidates of best cell lines will be determined. - Reviewers generally agreed that the proposal is at the exploratory stage and except for the proof of concept studies, the regulatory strategies are significantly under-developed. Qualifications of the PI - Reviewers agreed that the team has numerous strengths with previous experience in neurotrauma modeling, however, some strongly believed that inclusion of expertise in clinical neurotrauma is imperative. They advised that this critical element be addressed before implementing this protocol. - Both the PI and co-PI were viewed as experts in their respective fields, and the partnership was believed to offer a synergistic combination of both of their skills and interests. - Reviewers found the web based communication approach as novel and highly organized. Collaborations, Assets, Resources and Environment - No relevant concerns were highlighted by reviewers under this review criterion. Responsiveness to the RFA - No relevant concerns were highlighted by reviewers under this review criterion