UCSF Professors Arturo Alvarez-Buylla, Ph.D., Scott Baraban, Ph.D., and John Rubenstein, M.D., Ph.D., have shown in adult mammals that grafted, inhibitory interneuron progenitors can:
The work reveals the potential of cell-based therapies to treat epilepsy, while minimizing the risks and side effects associated with today’s treatments.
"Our work is ultimately geared to disease treatment, but there are a lot of unknowns in between where basic research plays a critical role,” said Alvarez-Buylla, a professor in the UCSF Department of Neurological Surgery and one of the world’s leading experts on neurogenesis.
Almost two decades ago, while at another institution, Alvarez-Buylla and his lab discovered that young neurons continue to migrate and incorporate into the brain’s olfactory bulb. The discovery helped overturn long-held beliefs that new neurons could not be incorporated into the functioning circuits of an adult brain. Subsequently, Alvarez-Buylla and a graduate student, Hynek Wichterle, found that when embryonic progenitor cells from the medial ganglionic eminence (MGE) were grafted into an adult brain, they migrated and integrated into multiple brain regions.
The work overlapped with a rich body of UCSF research on neuronal progenitors of the MGE. Since then, in addition to the epilepsy research, Alvarez-Buylla has worked with the UCSF lab of Arnold Kriegstein, M.D., Ph.D., to demonstrate that the MGE cells also can integrate into and modify neural circuits in regions of the brain involved in motor disorders.
The next big challenge is proving that this process can safely and effectively treat disease. For example, a common concern about using embryonic stem cells is that their plasticity increases the possibility that they will develop into tumors.
"But our recent work indicates that we can persuade the progenitors to make the right types of neurons," Alvarez-Buylla said. If those findings remain valid, the work has powerful implications for conditions beyond epilepsy, including Parkinson’s disease and mental illness.
The research of neurosurgeon Daniel Lim, M.D., Ph.D., is another example of collaborative, stem cell-based work. He brings the perspective of a practicing surgeon and basic scientist to two research paths that he hopes will converge to bring cell-based therapies to the patient's bedside as quickly as possible.
From the basic science side, in conjunction with the investigators above, Lim is pursuing a cell-based therapy for epilepsy that uses adult stem cells, rather than embryonic stem cells.
From the clinical side, Lim is developing novel surgical tools to transplant cells to the human brain.
"The syringe and needle devices we have today require multiple brain penetrations and don’t effectively distribute the cells,” Lim said. "We want to develop a device that can distribute cells to large brain areas through a single, initial brain penetration." He has obtained a $1.8 million California Institute for Regenerative Medicine grant to support a team of engineers, stem cell scientists and neurosurgeons who will design, produce and validate such a device.
Alvarez-Buylla said, "Medicine has its roots in a fascination with how things work, and this fascination still has an integral role in clinical practice.”
“I’m hopeful that the innovative mix of basic science and clinical science will help patients in unexpected ways,” Lim added.
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