title: In vivo proof-of-concept of removal of the huntingtin caspase cleavage motif-encoding exon 12 approach in the YAC128 mouse model of Huntington's disease.
abstract: Huntington's disease (HD) is a progressive autosomal dominant disease, caused by a CAG repeat expansion in the HTT gene, resulting in an expanded polyglutamine stretch at the N-terminal of the huntingtin protein. An important event in HD pathogenesis appears to be the proteolysis of the mutant protein, which forms N-terminal huntingtin fragments. These fragments form insoluble aggregates and are found in nuclei and cytoplasm of affected neurons where they interfere with normal cell functioning. Important cleavage sites are encoded by exon 12 of HTT. A novel approach is Htt protein modification through exon skipping, which has recently been proven effective both in vitro and in vivo. Here we report proof-of-concept of AON 12.1 in vivo using the YAC128 mouse model of HD. Our results support and encourage future longitudinal studies exploring the therapeutic effects of sustained infusions in the YAC128 mouse model.
authors.affiliation: Departments of Neurosurgery Maastricht University Medical Center, Maastricht, The Netherlands; Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands; European Graduate School of Neuroscience (EURON), The Netherlands. Electronic address: j.casacacarreira@maastrichtuniversity.nl.
authors.forename: João
authors.initials: J
authors.lastname: Casaca-Carreira
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, The Netherlands.
authors.forename: Lodewijk J A
authors.initials: LJA
authors.lastname: Toonen
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, The Netherlands; Department of Research & Development, uniQure, Amsterdam, The Netherlands.
authors.forename: Melvin M
authors.initials: MM
authors.lastname: Evers
authors.affiliation: Departments of Neurosurgery Maastricht University Medical Center, Maastricht, The Netherlands; Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands; European Graduate School of Neuroscience (EURON), The Netherlands.
authors.forename: Ali
authors.initials: A
authors.lastname: Jahanshahi
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, The Netherlands.
authors.forename: Willeke M C
authors.initials: WMC
authors.lastname: van-Roon-Mom
authors.affiliation: Departments of Neurosurgery Maastricht University Medical Center, Maastricht, The Netherlands; Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands; European Graduate School of Neuroscience (EURON), The Netherlands. Electronic address: y.temel@maastrichtuniversity.nl.
authors.forename: Yasin
authors.initials: Y
authors.lastname: Temel
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D020169:Caspases / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics*; D000071058:Huntingtin Protein / Q000235:genetics*; D006816:Huntington Disease / Q000201:enzymology / Q000235:genetics*; D008297:Male; D051379:Mice
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D020169:Caspases
keywords: Exon skipping; HD; Intracerebroventricular; Mouse; RNA