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Open Access Highly Accessed Review

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

Barbara J Bailus and David J Segal*

Author Affiliations

Genome Center, MIND Institute, and Department of Biochemistry and Molecular Medicine, University of California, Davis, CA 95616, USA

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BMC Neuroscience 2014, 15:76  doi:10.1186/1471-2202-15-76

Published: 19 June 2014

Abstract

Background

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 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.

Results

Here 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.

Conclusions

Artificial 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.

Keywords:
Artificial transcription factor; Engineered zinc finger; TALE; CRISPR; Gene regulation; Gene therapy; Blood–brain barrier; Angelman syndrome; Autism spectrum disorders