Small Molecule Therapeutic Discovery for Angelman Syndrome

PROJECT SUMMARY Angelman syndrome is a severe neurodevelopmental disorder caused by maternal allele deletions of UBE3A. In neurons, the paternal allele of UBE3A is epigenetically silenced. Unsilencing the paternal allele of UBE3A offers a potentially transformative opportunity for treating Angelman syndrome. We recently discovered a small molecule that unsilences the paternal allele of UBE3A in neurons cultured from Angelman syndrome model mice or from stem cells derived from Angelman syndrome individuals. When delivered noninvasively to Angelman syndrome model mice, this small molecule leads to brain-wide neuronal UBE3A protein expression without observable toxicity. We hypothesize that our small molecule approach can reverse Angelman syndrome phenotypes in mice, justifying its advance towards additional safety studies and future clinical trials. Towards developing this approach as a non-invasive treatment for Angelman syndrome, we propose to (1) establish rescue of behavioral and electrophysiological phenotypes in Angelman syndrome model mice, (2) identify the mechanism of action by which our small molecule produces unsilencing of paternal UBE3A, and (3) perform structure-activity-relationship studies to improve efficacy and maximize favorable pharmacology. By advancing the first small molecule treatment of Angelman syndrome, this research may lead to therapy yielding profound lifelong benefits for this patient population.