Premium
Personalized gene silencing therapeutics for Huntington disease
Author(s) -
Kay C.,
Skotte N.H.,
Southwell A.L.,
Hayden M.R.
Publication year - 2014
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.12385
Subject(s) - gene silencing , huntingtin , genetics , biology , huntington's disease , trinucleotide repeat expansion , allele , population , linkage disequilibrium , single nucleotide polymorphism , disease , gene , genotype , medicine , mutant , pathology , environmental health
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 ( HTT ). Silencing both expanded and normal copies of HTT may be therapeutically beneficial, but preservation of normal HTT expression is preferred. Allele‐specific methods can selectively silence the mutant HTT 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 HTT silencing faces challenges common to personalized genetic medicine, requiring novel solutions from clinical scientists and regulatory authorities.