The Neuroscience Center is pleased to announce that its Director, Dr. Mark Zylka, has received a new NIH R01 grant totaling $3 million over five years. The project, titled “UBE3A mosaicism and its relationship to Angelman syndrome phenotypes,” will investigate how the proportion of neurons expressing functional UBE3A influences the severity of Angelman syndrome (AS). The research team includes several faculty in the Center, namely Drs. Ben Philpot, Jason Stein, Guorong Wu, and Adam Hantman.
AS is a severe neurodevelopmental disorder caused by loss of the maternally inherited UBE3A allele. Although gene therapies that unsilence the dormant paternal UBE3A allele have shown partial rescue in mouse models, the precise relationship between the percentage of UBE3A-expressing neurons and phenotypic severity remains unknown.
Using complementary genetic approaches, the research team will systematically vary the fraction of UBE3A-positive neurons in the brain. Advanced light-sheet microscopy will map the percentage and spatial distribution of rescued neurons, while behavioral phenotyping will quantify therapeutic benefit. Parallel studies in chimeric mice will model natural mosaicism.
These experiments are expected to identify critical thresholds and brain regions for effective gene therapy and may offer broader insights for treating other neurogenetic and autism-spectrum disorders through mosaic gene restoration.