Drugs to awaken a paternal gene

Abstract

Genomic imprinting disorders arise owing to a loss of function of non-imprinted alleles expressed from one parent. In Angelman syndrome, a neurodevelopmental disorder caused by dysfunction of the maternal allele of the Ube3a gene, the paternal allele remains intact but is epigenetically silenced. Benjamin Philpot and colleagues perform an unbiased drug screen on mouse cortical neurons expressing fluorescent Ube3a and identify topoisomerase inhibitors that are capable of activating paternal Ube3a, including topotecan, a cancer therapeutic approved by the US Food and Drug Administration. When the drug is delivered in vivo, paternal Ube3a is activated in multiple regions of the brain, and effects persist for several weeks after drug cessation. This demonstrates a potential method for reactivating dormant alleles of imprinted genes, which may be a therapeutic strategy in disorders such as Angelman syndrome.