The prospect of molecular therapy for Angelman syndrome and other monogenic neurologic disorders.

Barbara J Bailus,David J Segal

doi:10.1186/1471-2202-15-76

Barbara J Bailus, David J Segal

Open Access

https://doi.org/10.1186/1471-2202-15-76

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Abstract

BackgroundAngelman syndrome is a monogenic neurologic disorder that affects 1 in 15,000 children, and is characterized by ataxia, intellectual disability, speech impairment, sleep disorders, and seizures. The disorder is caused by loss of central nervous system expression of UBE3A, a gene encoding a ubiquitin ligase. Current treatments focus on the management of symptoms, as there have not been therapies to treat the underlying molecular cause of the disease. However, this outlook is evolving with advances in molecular therapies, including artificial transcription factors a class of engineered DNA-binding proteins that have the potential to target a specific site in the genome.ResultsHere we review the recent progress and prospect of targeted gene expression therapies. Three main issues that must be addressed to advance toward human clinical trials are specificity, toxicity, and delivery.ConclusionsArtificial transcription factors have the potential to address these concerns on a level that meets and in some cases exceeds current small molecule therapies. We examine the possibilities of such approaches in the context of Angelman syndrome, as a template for other single-gene, neurologic disorders.

Highlights

Angelman syndrome is a monogenic neurologic disorder that affects 1 in 15,000 children, and is characterized by ataxia, intellectual disability, speech impairment, sleep disorders, and seizures
The disease is characterized as an autism spectrum disorder with individuals exhibiting severe mental and physical impairments, including a lack of speech and ataxia
The region encoding the gene UBE3A is epigenetically imprinted throughout neuronal brain cells, with the maternal allele being preferentially expressed and the paternal allele silenced [2]

Summary

Conclusions

The advances that have taken place in Angelman syndrome research in the last twenty years have made it an ideal candidate for targeted molecular therapy. Recent advances have verified an intact but silenced paternal UBE3A. ATFs have advanced in recent years, enabling regulation of specific gene transcripts in the human genome [58]. The delivery mechanisms of ATFs are still being optimized, but several options hold promise for crossing the blood brain barrier and long-term, gene-specific regulation. These advances may result in an eventual therapy for Angelman syndrome, allowing for the expression of paternal UBE3A and perhaps a full phenotypic rescue. Authors’ contributions BJB and DJS conceived, drafted, read, and approved the manuscript

21. Chamberlain SJ

27. Szyf M