학술논문
Antisense oligonucleotide-mediated disruption of HTT caspase-6 cleavage site ameliorates the phenotype of YAC128 Huntington disease mice.
Document Type
Academic Journal
Author
Kuijper EC; Department of Human Genetics, Leiden University Medical Center, the Netherlands. Electronic address: e.c.kuijper@lumc.nl.; Overzier M; Department of Human Genetics, Leiden University Medical Center, the Netherlands.; Suidgeest E; Department of Radiology, Leiden University Medical Center, the Netherlands.; Dzyubachyk O; Department of Radiology, Leiden University Medical Center, the Netherlands.; Maguin C; Université Paris-Saclay, Commissariat à l'Energie Atomique et aux Energies Alternatives, Centre National de la Recherche Scientifique, Molecular Imaging Research Center, Laboratoire des Maladies Neurodégénératives, France.; Pérot JB; Université Paris-Saclay, Commissariat à l'Energie Atomique et aux Energies Alternatives, Centre National de la Recherche Scientifique, Molecular Imaging Research Center, Laboratoire des Maladies Neurodégénératives, France; Institut du Cerveau - Paris Brain Institute, Sorbonne Université, France.; Flament J; Université Paris-Saclay, Commissariat à l'Energie Atomique et aux Energies Alternatives, Centre National de la Recherche Scientifique, Molecular Imaging Research Center, Laboratoire des Maladies Neurodégénératives, France.; Ariyurek Y; Department of Human Genetics, Leiden University Medical Center, the Netherlands.; Mei H; Department of Biomedical Data Sciences, Leiden University Medical Center, the Netherlands.; Buijsen RAM; Department of Human Genetics, Leiden University Medical Center, the Netherlands.; van der Weerd L; Department of Human Genetics, Leiden University Medical Center, the Netherlands; Department of Radiology, Leiden University Medical Center, the Netherlands.; van Roon-Mom W; Department of Human Genetics, Leiden University Medical Center, the Netherlands.
Source
Publisher: Academic Press Country of Publication: United States NLM ID: 9500169 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-953X (Electronic) Linking ISSN: 09699961 NLM ISO Abbreviation: Neurobiol Dis Subsets: MEDLINE
Subject
Language
English
Abstract
In Huntington disease, cellular toxicity is particularly caused by toxic protein fragments generated from the mutant huntingtin (HTT) protein. By modifying the HTT protein, we aim to reduce proteolytic cleavage and ameliorate the consequences of mutant HTT without lowering total HTT levels. To that end, we use an antisense oligonucleotide (AON) that targets HTT pre-mRNA and induces partial skipping of exon 12, which contains the critical caspase-6 cleavage site. Here, we show that AON-treatment can partially restore the phenotype of YAC128 mice, a mouse model expressing the full-length human HTT gene including 128 CAG-repeats. Wild-type and YAC128 mice were treated intracerebroventricularly with AON12.1, scrambled AON or vehicle starting at 6 months of age and followed up to 12 months of age, when MRI was performed and mice were sacrificed. AON12.1 treatment induced around 40% exon skip and protein modification. The phenotype on body weight and activity, but not rotarod, was restored by AON treatment. Genes differentially expressed in YAC128 striatum changed toward wild-type levels and striatal volume was preserved upon AON12.1 treatment. However, scrambled AON also showed a restorative effect on gene expression and appeared to generally increase brain volume.
Competing Interests: Declaration of Competing Interest WvRM discloses being employed by LUMC which has patents on exon skipping approaches for neurological disorders. In the past, some of these patents have been licensed to ProQR therapeutics. As co-inventor on these patents WvRM is entitled to a share of milestone payments and royalties. WvRM further discloses being ad hoc consultant for Accure Therapeutics and Herbert Smith Freehills. Remuneration for these activities is paid to the LUMC. LUMC also received funding for contract research from UniQure and Amylon Therapeutics. RAMB is member of the Scientific Advisory Council of the Oligonucleotide Therapeutics Society. ECK, MO, ES, OD, CM, JBP, JF, YA, HM and LvdW declare no conflict of interest.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of Competing Interest WvRM discloses being employed by LUMC which has patents on exon skipping approaches for neurological disorders. In the past, some of these patents have been licensed to ProQR therapeutics. As co-inventor on these patents WvRM is entitled to a share of milestone payments and royalties. WvRM further discloses being ad hoc consultant for Accure Therapeutics and Herbert Smith Freehills. Remuneration for these activities is paid to the LUMC. LUMC also received funding for contract research from UniQure and Amylon Therapeutics. RAMB is member of the Scientific Advisory Council of the Oligonucleotide Therapeutics Society. ECK, MO, ES, OD, CM, JBP, JF, YA, HM and LvdW declare no conflict of interest.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)