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Antisense Oligonucleotide Therapeutic Approach for Suppression of Ataxin-1 Expression: A Safety Assessment
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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452125/ https://www.ncbi.nlm.nih.gov/pubmed/32818920 http://dx.doi.org/10.1016/j.omtn.2020.07.030 |
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author | O’Callaghan, Brennon Hofstra, Bente Handler, Hillary P. Kordasiewicz, Holly B. Cole, Tracy Duvick, Lisa Friedrich, Jillian Rainwater, Orion Yang, Praseuth Benneyworth, Michael Nichols-Meade, Tessa Heal, Wesley Ter Haar, Rachel Henzler, Christine Orr, Harry T. |
author_facet | O’Callaghan, Brennon Hofstra, Bente Handler, Hillary P. Kordasiewicz, Holly B. Cole, Tracy Duvick, Lisa Friedrich, Jillian Rainwater, Orion Yang, Praseuth Benneyworth, Michael Nichols-Meade, Tessa Heal, Wesley Ter Haar, Rachel Henzler, Christine Orr, Harry T. |
author_sort | O’Callaghan, Brennon |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7452125 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-74521252020-09-09 Antisense Oligonucleotide Therapeutic Approach for Suppression of Ataxin-1 Expression: A Safety Assessment O’Callaghan, Brennon Hofstra, Bente Handler, Hillary P. Kordasiewicz, Holly B. Cole, Tracy Duvick, Lisa Friedrich, Jillian Rainwater, Orion Yang, Praseuth Benneyworth, Michael Nichols-Meade, Tessa Heal, Wesley Ter Haar, Rachel Henzler, Christine Orr, Harry T. Mol Ther Nucleic Acids Article 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. American Society of Gene & Cell Therapy 2020-07-25 /pmc/articles/PMC7452125/ /pubmed/32818920 http://dx.doi.org/10.1016/j.omtn.2020.07.030 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article O’Callaghan, Brennon Hofstra, Bente Handler, Hillary P. Kordasiewicz, Holly B. Cole, Tracy Duvick, Lisa Friedrich, Jillian Rainwater, Orion Yang, Praseuth Benneyworth, Michael Nichols-Meade, Tessa Heal, Wesley Ter Haar, Rachel Henzler, Christine Orr, Harry T. Antisense Oligonucleotide Therapeutic Approach for Suppression of Ataxin-1 Expression: A Safety Assessment |
title | Antisense Oligonucleotide Therapeutic Approach for Suppression of Ataxin-1 Expression: A Safety Assessment |
title_full | Antisense Oligonucleotide Therapeutic Approach for Suppression of Ataxin-1 Expression: A Safety Assessment |
title_fullStr | Antisense Oligonucleotide Therapeutic Approach for Suppression of Ataxin-1 Expression: A Safety Assessment |
title_full_unstemmed | Antisense Oligonucleotide Therapeutic Approach for Suppression of Ataxin-1 Expression: A Safety Assessment |
title_short | Antisense Oligonucleotide Therapeutic Approach for Suppression of Ataxin-1 Expression: A Safety Assessment |
title_sort | antisense oligonucleotide therapeutic approach for suppression of ataxin-1 expression: a safety assessment |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452125/ https://www.ncbi.nlm.nih.gov/pubmed/32818920 http://dx.doi.org/10.1016/j.omtn.2020.07.030 |
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