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Background  Angelman syndrome (AS) is a severe neurodevelopmental disorder lacking effective therapies. AS is caused by mutations in ubiquitin protein ligase E3A ( UBE3A ), which is genomically imprinted such that only the maternally inherited copy is expressed in neurons. We previously demonstrated that topoisomerase I (Top1) inhibitors could successfully reactivate the dormant paternal allele of  Ube3a  in neurons of a mouse model of AS. We also previously showed that one such Top1 inhibitor, topotecan, could unsilence paternal  UBE3A  in induced pluripotent stem cell-derived neurons from individuals with AS. Although topotecan has been well-studied and is FDA-approved for cancer therapy, its limited CNS bioavailability will likely restrict the therapeutic use of topotecan in AS. The goal of this study was to identify additional Top1 inhibitors with similar efficacy as topotecan, with the expectation that these could be tested in the future for safety and CNS bioavailability to assess their potential as AS therapeutics.    Methods  We tested 13 indenoisoquinoline-derived Top1 inhibitors to identify compounds that unsilence the paternal allele of  Ube3a  in mouse neurons. Primary cortical neurons were isolated from embryonic day 14.5 (E14.5) mice with a  Ube3a-YFP  fluorescent tag on the paternal allele ( Ube3a   m+/pYFP   mice) or mice that lack the maternal  Ube3a  allele and hence model AS ( Ube3a   m−/p+   mice). Neurons were cultured for 7 days, treated with drug for 72 h, and examined for paternal UBE3A protein expression by Western blot or fluorescence immunostaining. Dose responses of the compounds were determined across a log range of drug treatments, and cytotoxicity was tested using a luciferase-based assay.    Results  All 13 indenoisoquinoline-derived Top1 inhibitors unsilenced paternal  Ube3a . Several compounds exhibited favorable paternal  Ube3a  unsilencing properties, similar to topotecan, and of these, indotecan (LMP400) was the most effective based on estimated E max  (maximum response of unsilencing paternal  Ube3a ) and EC 50  (half maximal effective concentration).    Conclusions  We provide pharmacological profiles of indenoisoquinoline-derived Top1 inhibitors as paternal  Ube3a  unsilencers. All 13 tested compounds were effective at unsilencing paternal  Ube3a , although with variable efficacy and potency. Indotecan (LMP400) demonstrated a better pharmacological profile of  Ube3a  unsilencing compared to our previous lead compound, topotecan. Taken together, indotecan and its structural analogues are potential AS therapeutics whose translational potential in AS treatment should be further assessed.    Electronic supplementary material  The online version of this article (10.1186/s13229-018-0228-2) contains supplementary material, which is available to authorized users.

molecular autism

Characterization and structure-activity relationships of indenoisoquinoline-derived topoisomerase I inhibitors in unsilencing the dormant Ube3a gene associated with Angelman syndrome