The California Institute for Regenerative Medicine has awarded a $14 million grant to a research team led by Sergiu Pasca, MD, the Kenneth T. Norris Jr. Professor II of Psychiatry and Behavioral Sciences. The funding will support the team’s work elucidating the biology of and potential treatments for neurodevelopmental disorders using innovative models of the brain pioneered by Pasca’s lab.
For more than a decade, his lab has been creating 3D neural organoids derived from human pluripotent stem cells. Scientists can take a patient’s skin cells and chemically coax them in the lab, first into a stem-cell-like state and then to differentiate into various types of brain cells, which grow into an organoid. These brain organoids mimic some of the features and physiology of the human cerebral cortex (the seat of high-level cognitive functions like language and problem-solving) and other parts of the nervous system, and they contain the same genetics as the patient. Organoids of different parts of the brain can be fused together into what Pasca’s team termed assembloids.
In the last few years, Pasca’s lab has been transplanting human neural organoids into the brains of newborn rodents, where they thrive, mature and integrate into indigenous circuits. These models provide unprecedented access to human brain tissue in a living system and a rare window into the dysfunction that underlies neurodevelopmental disorders.
The researchers even demonstrated, in a proof-of-principle experiment in the transplant model, that a form of therapy could correct some of the defects underlying Timothy syndrome, a rare genetic disorder with severe cardiac and neurological symptoms.
With the new grant, Pasca, who is also the Bonnie Uytengsu and Family Director of the Stanford Brain Organogenesis Program and a CZ Biohub investigator, will lead a team employing these models to study neural circuit dysfunction — in particular, an imbalance of excitation and inhibition of electrical signals in the cerebral cortex. Such imbalance is thought to underly many neurodevelopmental disorders, both common and rare, including autism spectrum disorder and epileptic encephalopathies. By studying models of such disorders, and how molecular changes to ion channels and neurotransmitter receptors affect brain function, the researchers hope to discover strategies to correct such imbalances.
“This is an exciting time with the potential to open new paths toward mechanism-based therapies,” Pasca said. “This effort brings together complementary expertise on campus and off campus, including human stem cell neuroscience, genomics, clinical sciences, machine learning and circuit biology, to uncover divergent and shared mechanisms of neurodevelopmental disorders.”
The grant is among nine CIRM has awarded this year — a total of $111 million. CIRM is a state agency that funds stem cell and gene therapy research with the goal of accelerating treatments for patients with unmet medical needs.
