Molecular mechanisms and biomarkers of a candidate Angelman syndrome therapeutic
$200,000 – 2-years
Dr. Zylka’s lab will expand on the work previously funded by ASF that led to the identification of a family of topoisomerase inhibitors that can unsilence the paternal UBE3A gene. In order to learn more about this topoisomerase-linked phenomenon, this lab plans to conduct further experiments to understand the mechanisms whereby topoisomerase regulates UBE3A expression. They will use RNA interference to knock down topoisomerase proteins in the mouse and then evaluate subsequent UBE3A expression. They will analyze UBE3A antisense transcripts to determine how they are biomarkers for the effects of topoisomerase inhibitor actions. They also plan to determine antisense and sense transcript levels in active and in silenced neurons and they will evaluate genome wide expression of other known imprinted genes to see if they are also affected by these inhibitors. Knowing more about how topoisomerase inhibitors mechanistically regulate Ube3a expression could identify biomarkers that might then be used as clinical indicators of drug efficacy. Work by this investigator raises the exciting possibility that small molecule compounds could be used as an Angelman syndrome therapeutic.