Early Translational IV
$5 066 815
Spinal cord injury (SCI) affects 11,000 Americans/year & leaves >250,000 individuals with untreatable life-long disabilities. The economic cost of both acute & chronic care for these patients, as well as the loss of the productivity of typically young wage-owners & many of their family members (who must serve as caretakers), makes attempting to remediate this condition not only a humanitarian goal but also a national imperative. Clinically, recovering even 1-2 segments of function would be impactful & alleviate many of the medical complications that characterize SCI. This project is designed to test a multi-modal therapeutic approach to SCI that aims to modify the injured environment of the spinal cord (SC) to both promote repair & blunt those processes that inhibit repair. We also think we can also address certain therapeutic challenges that are unique to SCI -- e.g., loss of tissue & connectivity, cyst formation, scarring, vascular & neural disruption. We will marry stem cell biology to tissue engineering & gene therapy. Furthermore, we will test first in a clinically-relevant animal model, as proof-of-concept, human neural stem cells derived from human induced pluripotent stem cells (hIPSCs), recognizing that, ultimately, a patient’s own immunocompatible hIPSCs derived from his/her own cells should be used to avoid immunosuppressants. At completion of this study, we hope to begin IND-enabling studies.
Statement of Benefit to California:
Spinal cord injury (SCI) affects 11,000 Americans/year & leaves >250,000 individuals with untreatable life-long disabilities. The economic cost of both acute & chronic care for these patients, as well as the loss of the productivity of typically young wage-owners & many of their family members (who must serve as caretakers), makes attempting to remediate this condition not only a humanitarian goal but also a state and national imperative. Being able to reduce the degree of disability – even recouping a few segments of spinal cord function (e.g., bladder control, use of the thumb, spontaneous respirations) could make a vast humanitarian, social, and economic impact on entire families – not just the patient -- and hence the California economies. We wish to bring an approach to clinical practice that we feel may impact not only recently injured patients but, perhaps, even those who have been in wheel chairs a bit longer.
This application for a Development Candidate Award is focused on a combination product consisting of progenitor cells on a scaffold that would be implanted into the spinal cord to limit functional deficits after a spinal cord injury (SCI). The combination product is intended to modify the injured environment of the spinal cord to both promote repair and prevent processes that inhibit repair. The applicant proposes to combine two neural cell populations derived from human induced pluripotent stem cells (hiPSC; eventually patient derived) with a biodegradable scaffold, and each of the components in the combination product may be engineered to secrete neurotrophic factors. Milestones include iterative examination of functional efficacy of hiPSC-derived neural stem cells (NSC) in combination with the scaffold at multiple time points after injury in a rodent model of SCI; genetically engineering the NSC to secrete neurotrophic factors and repeating the studies in the rodent model; impregnating the scaffold with releasable neurotrophic factors and repeating the studies in the rodent model; adding a second hiPSC-derived neural cell type to the combination product and repeating the studies in the rodent model; and moving the best candidate combination products forward into a clinically relevant model of SCI. Objective and Milestones - The milestones are very detailed, but lack sufficient go/no go decision points that would be required to guide progressive narrowing of the candidate pool. - The Target Product Profile (TPP) described multiple possible development candidates. Rationale and Significance - Reviewers agreed that development of a therapeutic candidate that can promote recovery of function after SCI would be of great clinical importance. The multifunctional approach that the team proposes is rational, although reviewers described it as highly and unrealistically ambitious. - Reviewers appreciated that the research plan incorporates sophisticated analysis methods and progressive animal care practices. - While reviewers acknowledged that the studies proposed would add significant knowledge to the SCI field, the scientific and regulatory complexity of the planned combination product limited enthusiasm for its successful development into a translational candidate. Feasibility and Design - The scope of the proposal was viewed as too broad to be accomplished within the three year award window. - Reviewers questioned the clinical relevance of the acute treatment time points proposed in the rodent studies and suggested that the later administration time points could be more informative for translational development of the proposed combination product. - Reviewers expressed concern that the large number of control groups required per rodent study and the multiple endpoints proposed per study may limit the ability to effectively identify differences between combinatorial candidates. - It was unclear how appropriate cell doses and levels of neurotrophic factors would be chosen for inclusion in the combination product. Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team - The research team was viewed to be excellent, with extensive experience in neural stem cells, transplantation into SCI models and biomaterial development. Collaborations, Assets, Resources and Environment - The team’s institutional facilities are excellent, and all necessary resources for the project are readily available. Responsiveness to the RFA - The proposal is responsive to the RFA.