title: Huntingtin Haplotypes Provide Prioritized Target Panels for Allele-specific Silencing in Huntington Disease Patients of European Ancestry.
abstract: Huntington disease (HD) is a dominant neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin gene (HTT). Heterozygous polymorphisms in cis with the mutation allow for allele-specific suppression of the pathogenic HTT transcript as a therapeutic strategy. To prioritize target selection, precise heterozygosity estimates are needed across diverse HD patient populations. Here we present the first comprehensive investigation of all common target alleles across the HTT gene, using 738 reference haplotypes from the 1000 Genomes Project and 2364 haplotypes from HD patients and relatives in Canada, Sweden, France, and Italy. The most common HD haplotypes (A1, A2, and A3a) define mutually exclusive sets of polymorphisms for allele-specific therapy in the greatest number of patients. Across all four populations, a maximum of 80% are treatable using these three target haplotypes. We identify a novel deletion found exclusively on the A1 haplotype, enabling potent and selective silencing of mutant HTT in approximately 40% of the patients. Antisense oligonucleotides complementary to the deletion reduce mutant A1 HTT mRNA by 78% in patient cells while sparing wild-type HTT expression. By suppressing specific haplotypes on which expanded CAG occurs, we demonstrate a rational approach to the development of allele-specific therapy for a monogenic disorder.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Chris
authors.initials: C
authors.lastname: Kay
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Collins
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Niels H
authors.initials: NH
authors.lastname: Skotte
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Amber L
authors.initials: AL
authors.lastname: Southwell
authors.affiliation: Department of Psychiatry, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Warby
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Caron
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Crystal N
authors.initials: CN
authors.lastname: Doty
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Betty
authors.initials: B
authors.lastname: Nguyen
authors.affiliation: Neurogenetics Unit and Rare Disease Centre, IRCCS Neuromed Pozzilli (IS), Pozzilli, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Griguoli
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Ross
authors.affiliation: Neurogenetics Unit and Rare Disease Centre, IRCCS Neuromed Pozzilli (IS), Pozzilli, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Squitieri
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: mrh@cmmt.ubc.ca.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D000483:Alleles; D015870:Gene Expression; D018390:Gene Targeting; D015316:Genetic Therapy / Q000379:methods*; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000628:therapy*; D054643:INDEL Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger