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

Barbara J Bailus, David J Segal, Barbara J Bailus, David J Segal

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.

Figures

Figure 1
Figure 1
Epigenetically imprinted genes at the Angelman locus. The region of 15q11-13 shown is approximately that of the most common 5-Mb deletion. On the paternal allele, the green genes are expressed but the red genes are not. On the maternal allele, the imprint is reversed, green genes expressed, and red genes are not. Genes shown in blue are active on both the paternal and maternal chromosomes. Colored arrows indicate the direction of active transcription. The 600-kb brain-specific UBE3A-ATS transcript (indicated by black arrow) silences the paternal copy of UBE3A. Deletion of the maternal region therefore results in loss of UBE3A expression in the brain.
Figure 2
Figure 2
DNA-binding platforms for artificial transcription factors. (a) Each repeat module of an engineered zinc finger protein recognizes three base pairs of DNA. The VP64 transcriptional activation domain is shown in cyan. Other common effector domains include the KRAB repression domain. (b) Each repeat of a TALEN protein recognizes one base pair of DNA. A thymine base (red) just 5′ of the repeat-bound DNA site is preferred for high-affinity binding. (c) An engineered CRISPR system consists of a guide RNA (red strand with colored sections) that directs the Cas9 nuclease (light blue) to the target DNA. Mutation of the two-endonuclease domains (arrows with red X) produces a non-catalytic DNA-binding domain, to which an effector domain can be attached. The required protospacer adjacent motif (PAM), NGG, is shown 3′ to the target site.

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