Angelman syndrome (AS) is a genetic disorder characterized by developmental delay, absent speech, intellectual disability, severe epilepsy, ataxia, and abnormal sleep. AS is caused by mutations in or deletion of Ube3a, an E3 ubiquitin ligase that is expressed biallelically in most tissues but is monoallelically expressed in the brain. Maternal-specific expression of Ube3a in the brain is thought to be due to production of an antisense transcript that overruns the paternal copy of Ube3a in mice and humans. Mice with maternal-specific deletions of Ube3a model many of the neurodevelopmental symptoms associated with AS, including epilepsy, learning deficits, and motor abnormalities. Using a high-throughput, unbiased screen with neurons from a Ube3a- YFP knockin mouse, we identified several small molecules that unsilence the paternal Ube3a allele at nanomolar concentrations. We hypothesize that the physiological and behavioral dysfunctions associated with Angelman syndrome can be treated by unsilencing the paternal Ube3a allele in vivo with one of these drugs. In this proposal we will: (1) Test the hypothesis that our lead compound upregulates paternal Ube3a in vivo; (2) Test the hypothesis that our lead compound can rescue physiological and behavioral deficits in Angelman syndrome model mice; (3) Test the hypothesis that genetic knockdown/out of the molecular target of our lead compound unsilences paternal Ube3a; (4) Test the hypothesis that the expression of the Ube3a-sense and Ube3a-antisense transcript levels can be used as biomarkers of drug efficacy (i.e. Ube3a unsilencing). Our research could lead to the first pharmacological treatment for Angelman syndrome (an autism spectrum disorder), and indeed for any disorder caused by mutation of an imprinted gene.
The health care costs associated with treating Angelman syndrome are high, especially considering that individuals with this disorder live a normal lifespan but are incapable of caring for themselves. Our proposed research could provide the first treatment for Angelman syndrome and reduce the economic and medical burden associated with this severe epigenetic disorder.
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