title: Personalized gene silencing therapeutics for Huntington disease.
abstract: 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.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Kay
authors.forename: N H
authors.initials: NH
authors.lastname: Skotte
authors.forename: A L
authors.initials: AL
authors.lastname: Southwell
authors.forename: M R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D020868:Gene Silencing; D005799:Genes, Dominant / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005828:Genetics, Population; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000628:therapy*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects / Q000235:genetics; D057285:Precision Medicine / Q000379:methods* / Q000639:trends; D019680:Trinucleotide Repeat Expansion / Q000187:drug effects / Q000235:genetics
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins
keywords: Huntington disease; SNPs; antisense oligonucleotides; gene silencing; haplotypes; personalized medicine; population genetics; single-stranded siRNA; trinucleotide repeat