Antisense Oligonucleotide Therapeutic Approach for Suppression of Ataxin-1 Expression: A Safety Assessment.

Autor:	O'Callaghan B; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA., Hofstra B; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA., Handler HP; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA; Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, USA., Kordasiewicz HB; Ionis Pharmaceuticals, Carlsbad, CA, USA., Cole T; Ionis Pharmaceuticals, Carlsbad, CA, USA., Duvick L; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA., Friedrich J; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA., Rainwater O; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA., Yang P; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA., Benneyworth M; Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA., Nichols-Meade T; Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA., Heal W; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA., Ter Haar R; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA., Henzler C; Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, USA., Orr HT; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA. Electronic address: orrxx002@umn.edu.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2020 Sep 04; Vol. 21, pp. 1006-1016. Date of Electronic Publication: 2020 Jul 25.
DOI:	10.1016/j.omtn.2020.07.030
Abstrakt:	Spinocerebellar ataxia type 1 (SCA1) is a lethal, autosomal dominant neurodegenerative disease caused by a polyglutamine expansion in the ATAXIN-1 (ATXN1) protein. Preclinical studies demonstrate the therapeutic efficacy of approaches that target and reduce Atxn1 expression in a non-allele-specific manner. However, studies using Atxn1 -/- mice raise cautionary notes that therapeutic reductions of ATXN1 might lead to undesirable effects such as reduction in the activity of the tumor suppressor Capicua (CIC), activation of the protease β-secretase 1 (BACE1) and subsequent increased amyloidogenic cleavage of the amyloid precursor protein (APP), or a reduction in hippocampal neuronal precursor cells that would impact hippocampal function. Here, we tested whether an antisense oligonucleotide (ASO)-mediated reduction of Atxn1 produced unwanted effects involving BACE1, CIC activity, or reduction in hippocampal neuronal precursor cells. Notably, no effects on BACE1, CIC tumor suppressor function, or number of hippocampal neuronal precursor cells were found in mice subjected to a chronic in vivo ASO-mediated reduction of Atxn1. These data provide further support for targeted reductions of ATXN1 as a therapeutic approach for SCA1. (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu