At UCSF Benioff Children’s Hospital, David Rowitch, M.D., Ph.D., chief of Neonatology, is leading the first neural stem cell trial in the United States to treat a disease caused by lack of myelin. Lack of myelin is causative in neurological diseases such as multiple sclerosis and cerebral palsy.
This pioneering study focuses on the rare and fatal childhood disorder Pelizaeus-Merzbacher disease (PMD).
PMD patients cannot produce myelin because their oligodendrocytes, the brain cells that create myelin, lack a critical protein. An inherited disorder, PMD primarily affects boys and can show up during infancy, when the child exhibits neurological dysfunction. In the severe form of PMD, children may rely on breathing machines and feeding tubes, and they typically die before the age of 10. There is no known therapy.
"PMD kids have normal neurons and networks in the brain. They've just never had any myelin, Rowitch said. "If we can successfully replace their defective oligodendrocytes, we might restore normal brain function and decrease fatal outcomes and seizures."
In this phase I clinical trial, Nalin Gupta, M.D., Ph.D., chief of Pediatric Neurosurgery, is transplanting neural stem cells into the brains of four PMD patients, 6 months to 5 years of age, primarily to see whether the approach is safe.
The researchers will also use magnetic resonance imaging to observe whether the cells develop into oligodendrocytes that form myelin, and then they will assess neurological function. In animal studies, these neural stem cells did migrate to where they were needed, developed into oligodendrocytes and formed myelin.
The study is being conducted in collaboration with Palo Alto-based StemCells Inc., whose proprietary purified human neural stem cells are being used in the trial. If the data from this first human study in PMD demonstrate that the cells and the procedure are safe, the trial could lead to future studies with other PMD patients.
"Although this trial is only a first, small step, it represents an important milestone," Rowitch said. "This research could potentially provide proof of concept for a cell-based approach to treating other demyelinating disorders, including the repair of demyelinating plaque in MS."
UCSF neurologist Hans-Christian von Budingen, M.D., is also working to defeat dymelinating disorders, in his case by examining cell-based model systems.
"We know there is a complex genetic background in MS patients that supports development of the disease, and we are trying to capture that picture," von Budingen said.
He is focused on B cells, whose production of antibodies is suspected to play a role in MS. His lab is using induced pluripotent stem cells derived from MS patients to generate different types of brain cells, and then studying the reaction of B-cell antibodies to these various cells.
His work builds on groundbreaking clinical research by Neurology department Chair Stephen Hauser, M.D. In 2008, Hauser published a piece in the New England Journal of Medicine that established that the drug rituximab, which depletes B cells, is effective in bringing down disease activity in MS patients.
"We think that certain B cells recognize targets in the brain, and that the rituximab therapy may break the link that’s required for generating an immune response," von Büdingen said. "If we can find what the antibodies bind to in MS patients, we could perhaps generate a disease-specific therapy that will support regeneration and repair."
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