New treatments for Angelman syndrome?

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Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Huang HS et al. Nature. 2011 Dec 21.
Angelman syndrome is a genetic disorder characterized by severe developmental delay, severe speech impairment, gait ataxia and/or tremulousness of the limbs, as well as typical behaviour. It is an imprinting disorder caused by changes in the maternal allele of UBE3A gene. In neurons, the paternal allele of UBE3A is intact but epigenetically silenced. This study explored the possibility that Angelman syndrome could be treated by activating this silenced allele to restore functional UBE3A protein. Using an unbiased, high-content screen in primary cortical neurons from mice (AS animal model), Huang et al. identified 12 topoisomerase I inhibitors and 4 topoisomerase II inhibitors that unsilence the paternal UBE3A allele. This study also showed that the unsilenced paternal allele produces a functional protein. Topoisomerase inhibitors appear to regulate UBE3A gene expression through a transcriptional mechanism (not by affecting the methylation status). The in vivo experiments performed on adult mice suggest that transient topoisomerase inhibition may have long-standing effects on gene expression. This is an example of regaining gene function without doing gene therapy. The researchers have not yet examined the effect of treatment on behavior of mice.

Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Huang et al. Nature. 2011 Dec 21;481(7380):185-9. PMID: 22190039

posted by Yannis Trakadis MD, MSc

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