Basic Biology IV
Myelin is a substance that coats that processes of nerves allowing for efficient conduction of the nervous impulse, which is important for communication between different areas of the brain and control of the body movements. The myelin disorder Multiple sclerosis is the most common neurological disability affecting young adults; cerebral palsy is affecting increasing numbers of preterm infants and leads to lifelong problems in body movements. Can myelin be restored to patients with these conditions? Here, investigators have focused on a human disease called Pelizaeus-Merzbacher disease (PMD), in which development of myelin fails leading to profound neurodevelopmental disability and death. The investigators will take small samples of cells from the skin and convert them into cells that can produce myelin. First, this will allow us to determine why myelin fails to form in these patients. Secondly, we will correct the gene mutation responsible for PMD and determine whether gene correction results in production of functional myelin. These studies may point the way to more effective therapies for patients with PMD. If successful, this project will provide proof-of-concept for cell-based therapies in myelin disorders with implications for multiple sclerosis and cerebral palsy.
Statement of Benefit to California:
This project will further establish the prominence of California as a leader in cell-based therapies for myelin disorders. Multiple sclerosis (MS) and cerebral palsy (CP) have been identified by CIRM as high priority disease targets. California biotech companies are already engaged in phase I studies for cell-based therapies for providing myelin in the congenital leukodystrophy Pelizaeus-Merzbacher disease (PMD) as well as spinal cord injury. Further expertise and optimization of cell-based therapies for myelin disorders could further the objectives of California biotech. Conditions such as PMD and transverse myelitis, as well as optic neuritis in MS are examples of disorders in which cell-based therapies might reasonably be applied within the next decade. Expertise in the state of California, with respect to these important disorders, can further be marshalled through training and opportunities for research provided by a CIRM basic biology award. There is a great momentum that has already resulted in integration of biomedical researchers from a variety of fields, including basic glial biology, neuroradiology and pediatric neurology, to foster development of phase I and phase II studies focused on myelin disorders. Thus, California is poised to emerge as a world leader in the implementation of cell-based therapies for myelin disorders led by engaged academic investigators and biotechnology corporations in the State.
This proposal is focused on the development of an induced pluripotent stem cell (iPSC) model of Pelizaeus-Merzbacher disease (PMD), a congenital, pediatric neurodegenerative disease of the myelin sheath surrounding neurons. The applicant proposes three Specific Aims: (1) to generate iPSCs from PMD patients with identified genetic mutations as well as iPSCs in which these mutations have been corrected; (2) to differentiate these iPSCs into oligodendrocytes and oligodendrocyte precursor cells (OPCs); and (3) to test the engraftment, function and safety of these differentiated cells in two animal models. Significance and Innovation - The proposal is not focused on basic cellular or molecular mechanisms of PMD. The tools generated would be valuable in mechanistic studies, but these studies are not specifically proposed. - While PMD is rare, other leukodystrophies are more common and hypomyelination is a fundamental problem in even more common diseases such as multiple sclerosis and cerebral palsy. - Developing a source of oligodendrocytes to treat hypomyelinating disease is a significant goal and could potentially have a clinical impact. Feasibility and Experimental Design - The application does not present substantial or compelling preliminary data demonstrating differentiation of iPSCs to OPCs or gene correction, which was considered the major weakness in the proposal. - The experimental design is logical but not particularly ambitious. - Aim 3, involving transplantation of OPCs into animal models, is the strength of the research plan and could produce important proof-of-concept data. Principal Investigator (PI) and Research Team - The PI is an outstanding researcher and expert in glial development and diseases of myelination. The PI has a long track record of success and strong publication record. - The Partner PI’s team includes clinicians and scientists who will provide access to PMD patient fibroblasts, reprogramming technology at a core facility, and one of the animal models. - Some reviewers were not convinced that the collaboration with the Partner PI is critical to the success of the project, as the PI also has access to PMD patient fibroblasts. Responsiveness to the RFA - The proposal is not fully responsive to the RFA because it does not focus on elucidating basic molecular and cellular mechanisms.