title: In vivo evaluation of candidate allele-specific mutant huntingtin gene silencing antisense oligonucleotides.
abstract: Huntington disease (HD) is a dominant, genetic neurodegenerative disease characterized by progressive loss of voluntary motor control, psychiatric disturbance, and cognitive decline, for which there is currently no disease-modifying therapy. HD is caused by the expansion of a CAG tract in the huntingtin (HTT) gene. The mutant HTT protein (muHTT) acquires toxic functions, and there is significant evidence that muHTT lowering would be therapeutically efficacious. However, the wild-type HTT protein (wtHTT) serves vital functions, making allele-specific muHTT lowering strategies potentially safer than nonselective strategies. CAG tract expansion is associated with single nucleotide polymorphisms (SNPs) that can be targeted by gene silencing reagents such as antisense oligonucleotides (ASOs) to accomplish allele-specific muHTT lowering. Here we evaluate ASOs targeted to HD-associated SNPs in acute in vivo studies including screening, distribution, duration of action and dosing, using a humanized mouse model of HD, Hu97/18, that is heterozygous for the targeted SNPs. We have identified four well-tolerated lead ASOs that potently and selectively silence muHTT at a broad range of doses throughout the central nervous system for 16 weeks or more after a single intracerebroventricular (ICV) injection. With further validation, these ASOs could provide a therapeutic option for individuals afflicted with HD.
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: 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: ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Holly B
authors.initials: HB
authors.lastname: Kordasiewicz
authors.affiliation: ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Østergaard
authors.affiliation: ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Watt
authors.affiliation: Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, Washington, USA.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Carroll
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: Erika B
authors.initials: EB
authors.lastname: Villanueva
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: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Yuanyun
authors.initials: Y
authors.lastname: Xie
authors.affiliation: ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Freier
authors.affiliation: ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Swayze
authors.affiliation: ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Punit P
authors.initials: PP
authors.lastname: Seth
authors.affiliation: ISIS Pharmaceuticals, Carlsbad, California, USA.
authors.forename: Clarence Frank
authors.initials: CF
authors.lastname: Bennett
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: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D020868:Gene Silencing; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D007267:Injections; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D050505:Mutant Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D017207:Rats, Sprague-Dawley; D013873:Thionucleotides / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides
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