title: A fully humanized transgenic mouse model of Huntington disease.
abstract: Silencing the mutant huntingtin gene (muHTT) is a direct and simple therapeutic strategy for the treatment of Huntington disease (HD) in principle. However, targeting the HD mutation presents challenges because it is an expansion of a common genetic element (a CAG tract) that is found throughout the genome. Moreover, the HTT protein is important for neuronal health throughout life, and silencing strategies that also reduce the wild-type HTT allele may not be well tolerated during the long-term treatment of HD. Several HTT silencing strategies are in development that target genetic sites in HTT that are outside of the CAG expansion, including HD mutation-linked single-nucleotide polymorphisms and the HTT promoter. Preclinical testing of these genetic therapies has required the development of a new mouse model of HD that carries these human-specific genetic targets. To generate a fully humanized mouse model of HD, we have cross-bred BACHD and YAC18 on the Hdh(-/-) background. The resulting line, Hu97/18, is the first murine model of HD that fully genetically recapitulates human HD having two human HTT genes, no mouse Hdh genes and heterozygosity of the HD mutation. We find that Hu97/18 mice display many of the behavioral changes associated with HD including motor, psychiatric and cognitive deficits, as well as canonical neuropathological abnormalities. This mouse line will be useful for gaining additional insights into the disease mechanisms of HD as well as for testing genetic therapies targeting human HTT.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada V5Z 4H4.
authors.forename: Amber L
authors.initials: AL
authors.lastname: Southwell
authors.forename: Simon C
authors.initials: SC
authors.lastname: Warby
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Carroll
authors.forename: Crystal N
authors.initials: CN
authors.lastname: Doty
authors.forename: Niels H
authors.initials: NH
authors.lastname: Skotte
authors.forename: Weining
authors.initials: W
authors.lastname: Zhang
authors.forename: Erika B
authors.initials: EB
authors.lastname: Villanueva
authors.forename: Vlad
authors.initials: V
authors.lastname: Kovalik
authors.forename: Yuanyun
authors.initials: Y
authors.lastname: Xie
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Pouladi
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Collins
authors.forename: X William
authors.initials: XW
authors.lastname: Yang
authors.forename: Sonia
authors.initials: S
authors.lastname: Franciosi
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D020868:Gene Silencing; D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000523:psychology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D045442:Rotarod Performance Test