Disease Team Planning
Cerebral palsy is a group of brain diseases which produce chronic motor disability in children. This group demonstrates easily identifiable clinical findings, and much of their injury is to developing oligodendrocytes, the myelinating cells in the brain, and cerebral white matter. Periventricular leukomalacia is the predominant pathology of brain injury in premature infants, and the most common cause of cerebral palsy. Periventricular leukomalacia affects up to 50% of the 56,000 premature infants born in the U.S. every year, yet currently no therapy exists for this serious human disorder. 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 for the development of a cell-based therapy for cerebral palsy. 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 be exploiting novel features of oligodendrocyte differentiation to improve our ability to generate oligodendrocyte lineage cells from human embryonic stem cells (federally sanctioned and nonsanctioned) for transplantation. 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: basic research in human embryonic stem cell biology and 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:
Human embryonic stem cell (hESC) represents a powerful therapeutic tool for regenerative medicine. Existing strategies for stem cell based therapies include both strategies to replace lost cells and to augment regeneration after injury, but most of these efforts have emphasized the role of undifferentiated stem cells in treatment despite the realization that the main nexus of injury in many neurological diseases, such as periventricular leukomalacia in premature infants leading to cerebral palsy, is frequently a differentiated cell type – the oligodendrocyte. This proposal will use recent insights into the development of oligodendrocytes from the laboratories to improve production of oligodendrocytes from hESCs, 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 The applicant proposes to form a team of scientists whose goal will be to develop a cell-based therapy for the treatment of patients cerebral palsy (CP), and in particular periventricular leukomalacia (PVL). CP represents a group of diseases resulting from hypoxic injuries to the brain near or around birth, particularly in premature infants, causing significant and permanent motor disability presenting in young children and persisting throughout life. In part, CP is due to loss of oligodendrocytes (OLs) in the periventricular area of the brain. Since there is a lack of reproducible methods for isolating OLs from human embryonic stem cells (hESCs), much of the proposed work will be aimed at identifying regulatory factors involved in the differentiation of OL precursors. The investigators propose to use an established animal model to test and develop protocols to use OLs derived from hESCs to ameliorate brain damage after hypoxic encephalopathy. They propose to use oligodendrocyte-based cell therapy in preclinical models of cerebral palsy and to use functional outcomes and imaging to asses whether cell transplantation is clinically effective, and then to progress this work toward human clinical applications. The significance of the work is high. CP is a fairly common neurological condition with few existing therapeutic options, therefore strategies designed to improve neurological functioning in CP are to be encouraged. In addition, successful approaches to this disease could easily translate into therapies for other disorders of myelination affecting children and adults. However, reviewers felt that the field and the applicant’s work were not mature enough to merit a disease team approach at this time. Given the paucity of experimental evidence, reviewers commented that it is highly uncertain that this cell therapy approach will be translatable to the clinic in the next five years. Reviewers noted that the applicant is actively working on strategies to isolate, characterize and expand OLs from embryonic stem cells (ESCs), which reviewers agreed was an important research goal in the field. This work appears to be in progress and the applicant has good experience in oligodendrocyte biology, but the project is not ready for a clinical trial. The applicant proposes to test the efficacy of these cells in an immune deficient mouse model of CP. While the results will be interesting, they will not necessarily provide useful information about dosing, delivery, or engraftment of these ES-derived oligodendrocytes in humans. Thus reviewers felt that this work lacked an essential translational component, that of upscaling, validation, and safety testing. Reviewers were also concerned about the viability of the team. The applicant is a newly-appointed investigator with a keen interested in this area that appears to be establishing a track record of basic research accomplishments, and is obviously working hard on the ES-derived OLs. S/he is surrounded by a laudable group of senior investigators who are potential competitors, but it is not clear that the applicant is experienced enough to lead this sort of investigative team, and the proposed planning approach was not strong enough to reassure the reviewers in this regard. Reviewer Synopsis The applicant plans to use oligodendrocytes or their progenitors as a therapy for cerebral palsy, and in particular periventricular leukomalacia (PVL). This is based on the observation that ischemia in the newborn rat pup leads to a loss of oligodendrocytes (OLs). We lack a reproducible method of isolating OLs from hESCs and so much of their work will be in regard to identifying regulating factors in the differentiation of OL precursors from hESCs. The applicant will determine whether hESC-derived OLs are capable of preventing white matter damage in their rodent model prior to planning a human clinical trial. The labeled cells will be followed in the model by MRI and the effect on myelination studied morphologically and the behavioral outcome determined. Reviewer One Comments Concept: The PI proposes to form a team of scientists whose goal will be to develop cell-based therapy for the treatment of patients with cerebral palsy (CP). CP represents a group of diseases resulting from hypoxic injuries to the brain near or around birth, particularly in premature infants, causing significant and permanent motor disabilities presenting in young children and persisting throughout life. In part, CP is due to loss of oligodendrocytes in the periventricular area of the brain. These investigators propose to use their established animal model to test and develop protocols to use oligodendrocytes, derived from embryonic stem cells (ESCs), to ameliorate brain damage after hypoxic encephalopathy. It appears that the principal investigator (PI) is actively working on strategies to isolate, characterize and expand oligodendrocytes from ES cells. This work appears to be in progress but not ready for a clinical trial. The PI also proposes to test the efficacy of these cells in an immune deficient mouse model of CP. While this will be interesting, it will not necessarily provide useful information about dosing, delivery, or engraftment of these ES-derived oligodendrocytes in human. Thus I think an interim step may be missing from this work, that of upscaling, validation and safety testing. If completed, this work could be highly significant because successful approaches in this disease could easily translate into therapies for other disorders of myelination affecting children and adults. Principal Investigator: The PI is a young investigator with a keen interest in this area. He appears to be establishing a track record of basic research accomplishments in the area and is obviously working hard on the ES-derived oligodendrocytes. He is surrounded by a laudable group of senior investigators, but it is not clear that he is experienced enough to lead an investigative team. Planning Approach: There is little detail about the actual plans for development, especially as they relate to the development of human clinical trials. Reviewer Two Comments Concept: This proposal is based on a cell based therapeutic strategy for the treatment of cerebral palsy. The applicants propose to use oligodendrocytes derived from human embryonic stem cells in animal models of cerebral palsy. Cerebral palsy is a fairly common neurological condition in which currently there is little if any therapeutic options, therefore strategies designed to improve neurological functioning in cerebral palsy are to be encouraged. Principal Investigator: The PI is a newly appointed faculty member at University of California Davis, who has, nevertheless, a very good track record in neurobiology, particularly in the area of oligodendrocyte cell biology and neuronal damage. He has established animal based models of cerebral palsy and he has assembled a team of experts in the field of animal models of neural disease in human embryonic stem cell biology. Planning Approach: The applicants propose to use oligodendrocyte based cell therapy in preclinical models of cerebral palsy and to use functional outcomes and imaging to asses whether cell transplantation is clinically effective, and then to progress this work toward human clinical applications. However given the paucity of experimental evidence, is highly uncertain the extent to which this is translatable into clinical applications in the next five years. Reviewer Three Comments Concept: There has been extensive research on the cellular susceptibility within developing white matter in rodent models of ischemia. There is strong evidence that OLs are susceptible and perhaps preferentially, to ischemia in the newborn brain. What is missing is whether replacing OPCs will prevent or repair damaged white matter. A reliable and reproducible method of isolating and culturing OPCs from hESCs is missing according to the applicant and so much of their efforts will go into defining new procedures to accomplish this. If successful, this would have significance for other CNS diseases where a source of human OPCs is sought. It should be noted however that in his proposal in the new cell line RFA he shows good evidence of oligodendrocyte differentiation from hESC. Principal Investigator: As he defines, the PI is a young and very active investigator with good funding and quite a strong publication track record. His training was at Harvard in a leading lab on the pathophysiology of PVL. He is located at UC Davis where there is significant critical mass in basic stem cell biology and translational efforts in taking stem cells to the clinic. He has the technical expertise to carry out what will likely be proposed. He is not a leader in the field yet and his junior status perhaps raises a question about his ability to organize and lead the team. Planning Approach: This is not a strength of the proposal. The PI identifies the key personnel but gives no detail on how they will achieve their objectives with the exception of identifying each of their specialties. I think this is a reflection of his junior status. He notes that David Rowitch is involved in animal modeling and as far as I know, he has not published anything on this.