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.