Personalized gene silencing therapeutics for Huntington disease. (11th April 2014)

• Record Type: Journal Article
• Authors: Kay, C.; Skotte, N.H.; Southwell, A.L.; Hayden, M.R.
• Is Part Of: Clinical genetics. Volume 86:Number 1(2014:Jul.)
• Page Start: 29
• Page End: 36
• Publication Date: 2014-04-11
• Subjects: Medical genetics -- Periodicals; 616.0420
• DOI: 10.1111/cge.12385
• Languages: English
• ISSNs: 0009-9163

Abstract

<abstract abstract-type="main" id="cge12385-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p id="cge12385-para-0001">Gene silencing offers a novel therapeutic strategy for dominant genetic disorders. In specific diseases, selective silencing of only one copy of a gene may be advantageous over non‐selective silencing of both copies. Huntington disease (HD) is an autosomal dominant disorder caused by an expanded CAG trinucleotide repeat in the Huntingtin gene (<italic>HTT</italic>). Silencing both expanded and normal copies of <italic>HTT</italic> may be therapeutically beneficial, but preservation of normal <italic>HTT</italic> expression is preferred. Allele‐specific methods can selectively silence the mutant <italic>HTT</italic> transcript by targeting either the expanded CAG repeat or single nucleotide polymorphisms (SNPs) in linkage disequilibrium with the expansion. Both approaches require personalized treatment strategies based on patient genotypes. We compare the prospect of safe treatment of HD by CAG‐ and SNP‐specific silencing approaches and review HD population genetics used to guide target identification in the patient population. Clinical implementation of allele‐specific <italic>HTT</italic> silencing faces challenges common to personalized genetic medicine, requiring novel solutions from clinical scientists and regulatory authorities.</p> </abstract>