title: Allele-specific suppression of mutant huntingtin using antisense oligonucleotides: providing a therapeutic option for all Huntington disease patients.
abstract: Huntington disease (HD) is an inherited, fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The mutant protein causes neuronal dysfunction and degeneration resulting in motor dysfunction, cognitive decline, and psychiatric disturbances. Currently, there is no disease altering treatment, and symptomatic therapy has limited benefit. The pathogenesis of HD is complicated and multiple pathways are compromised. Addressing the problem at its genetic root by suppressing mutant huntingtin expression is a promising therapeutic strategy for HD. We have developed and evaluated antisense oligonucleotides (ASOs) targeting single nucleotide polymorphisms that are significantly enriched on HD alleles (HD-SNPs). We describe our structure-activity relationship studies for ASO design and find that adjusting the SNP position within the gap, chemical modifications of the wings, and shortening the unmodified gap are critical for potent, specific, and well tolerated silencing of mutant huntingtin. Finally, we show that using two distinct ASO drugs targeting the two allelic variants of an HD-SNP could provide a therapeutic option for all persons with HD; allele-specifically for roughly half, and non-specifically for the remainder.
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: ISIS Pharmaceuticals, Carlsbad, California, United States of America.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Østergaard
authors.affiliation: Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, Washington, United States of America.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Carroll
authors.affiliation: Center for Advanced Research in Sleep Medicine, Department of Psychiatry, University of Montréal, Montréal, Quebec, 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: 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: Eugenia
authors.initials: E
authors.lastname: Petoukhov
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Kuljeet
authors.initials: K
authors.lastname: Vaid
authors.affiliation: ISIS Pharmaceuticals, Carlsbad, California, United States of America.
authors.forename: Holly
authors.initials: H
authors.lastname: Kordasiewicz
authors.affiliation: ISIS Pharmaceuticals, Carlsbad, California, United States of America.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Watt
authors.affiliation: ISIS Pharmaceuticals, Carlsbad, California, United States of America.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Freier
authors.affiliation: ISIS Pharmaceuticals, Carlsbad, California, United States of America.
authors.forename: Gene
authors.initials: G
authors.lastname: Hung
authors.affiliation: ISIS Pharmaceuticals, Carlsbad, California, United States of America.
authors.forename: Punit P
authors.initials: PP
authors.lastname: Seth
authors.affiliation: ISIS Pharmaceuticals, Carlsbad, California, United States of America.
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.affiliation: ISIS Pharmaceuticals, Carlsbad, California, United States of America.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Swayze
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D015195:Drug Design; D004622:Embryo, Mammalian; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D061251:Primary Cell Culture; D034622:RNA Interference; D013329:Structure-Activity Relationship
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense