Disease Team Therapy Planning I
We propose to assemble a multidisciplinary team of scientists and clinicians in pursuit of human iPS cell-based therapy for cerebral palsy. Cerebral palsy is a group of neurological diseases which produce chronic motor disability in children. This group demonstrates easily identifiable clinical findings, and much of their injury is to oligodendrocyte progenitors, the myelinating cells in the brain, in the cerebral white matter. Although oligodendrocyte progenitors are the cerebral white matter cells that are preferentially damaged in periventricular leukomalacia in premature infants leading to cerebral palsy, stem cell-derived oligodendrocyte progenitors have not been tested for their efficacy in preclinical trials. The primary goal here is to facilitate the exploration of a method of integrating and organizing high quality basic, translational and clinical stem cell research in a team setting, and to prepare research and management plans that can lead to clinical trials. A stem cell-based approach is very attractive for cerebral palsy, perhaps representing the best hope for medical breakthroughs that will reduce human suffering from this devastating disease. We will establish preclinical proof-of-concept in animal models that we have established, determine whether histology and neuromotor behavior are correlated on the same animals, and seek to image and track the grafted cells using MRI-detectable markers. We will foster coordination and collaboration among members of the Disease Team. The planning process will involve all team participants in addressing the objectives and translational potential of the research. The team will include multiple components and members with the relevant expertise: derivation of oligodendroglia, animal modeling, transplantation and immunology, project management, safety and toxicology, process development, quality control and assurance, regulation of biomedical products, and the preparation for clinical trials. Given the compelling evidence supporting the feasibility of the proposed concept and the underlying scientific approach, this planning award will allow us to put together the expertise, resources, services and technologies from different areas to move the research forward all the way to clinical trials. Taking an innovative disease team approach has the potential to advance therapies into the clinic more rapidly.
Statement of Benefit to California:
This proposal will use recent insights into the development of oligodendrocytes from the laboratories to improve production of oligodendrocyte progenitors from human iPS cells, and test whether these cells can improve the clinical outcome after transplantation in established animal model of periventricular leukomalacia leading to cerebral palsy. This effort represents the first step to translating the basic fundamental understanding of oligodendrocyte development into viable therapies for a serious human disease that is major burden on the citizens of California and worldwide. In addition, the proposed research will also benefit Californian in many other ways. It will result in development of novel technologies that will be broadly applicable to study stem cells and development of stem cell-based therapies, will help boost stem cell-based biotechnology industry in California, and will help position us and other Californian scientists at the forefront of stem cell research and medicine. It will increase experience and knowledge of stem cells among residents of California. It will contribute to the California education and health care systems by training undergraduate, graduate and postdoctoral students into highly skilled stem cell biologists. This project involves cooperation between multiple laboratories with complementary expertise. The interaction will facilitate skill exchange and staff training in cutting edge multidisciplinary approaches.
EXECUTIVE SUMMARY Project Synopsis This Planning Award proposal focuses on an induced pluripotent stem cell (iPSC)-derived cell therapy for periventricular leukomalacia (PVL) leading to cerebral palsy. PVL is a leading cause of cerebral palsy and is characterized by damage to cerebral white matter, which consists of cells called oligodendrocytes that produce myelin. The applicant proposes to develop allogeneic iPSC-derived oligodendrocyte progenitor cells as a cell replacement therapy for PVL leading to cerebral palsy. For the Research Award, the applicant proposes to complete IND-enabling preclinical studies and submit an Investigational New Drug (IND) application to the Food and Drug Administration (FDA) and conduct a Phase I/IIa clinical trial following approval of the IND. Significance and Impact - The potential impact of this particular proposal is unclear, given the early stage of development of the therapeutic candidate and the lack of feasibility of the draft project plan. - There is unmet medical need in the proposed patient population and development of a stem cell therapy for PVL leading to cerebral palsy could be impactful if successfully developed, as there are currently no effective, restorative therapies for these patients. Project Rationale and Feasibility - The applicant does not present sufficient proof-of-concept efficacy data with the proposed development candidate to support first-in-human clinical trials. - The rationale for using allogeneic iPSCs is unclear. Allogeneic iPSCs are not necessarily preferable to autologous iPSCs and could require patient immunosuppression, something not discussed in the proposal. Reviewers suggested that the applicant consider developing autologous iPSCs, as the lesions associated with PVL are not particularly time-sensitive, so the additional time required for autologous cell production should not be an issue. - The feasibility of completing the proposed preclinical and clinical studies in four years is doubtful, given the lack of proof-of-concept data, the lack of a definitive route of administration, and the poorly defined clinical trial parameters. - The proposed Phase I/IIa trial is vaguely outlined, with few details provided on the proposed patient population, specifically the targeted age of intervention or efficacy endpoints. It was noted that neurocognitive decline is a questionable inclusion criterion, as it is generally not seen in these patients. - No details are provided on methods for assessing biodistribution or cell tracking. - The rationale for pursuing cell-based therapies for PVL leading to cerebral palsy is strong, and reviewers encouraged development of this approach. Principal Investigator (PI) and Planning Leader - The PI is involved primarily in preclinical research and does not have experience translating this research to the clinic or running a human clinical trial. - While reviewers recognized that a major purpose of the Planning Award is to enable assembly of a strong team, they noted that the input of experts in neuroimaging and clinical trial methodology would have strengthened the proposal. - No Planning Leader is listed in the application.
- PROGRAMMATIC REVIEW
- This application was brought up for discussion during the programmatic portion of the review. Reviewers acknowledged the programmatic value of funding research into cell therapies for cerebral palsy but decided that this proposal is at a stage more appropriate for an Early Translational RFA. No motion was made.
- Andrew Balber