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Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease

Huntington disease (HD) is a fatal neurodegenerative disease caused by a pathogenic expansion of a CAG repeat in the huntingtin (HTT) gene. There are no disease-modifying therapies for HD. Artificial microRNAs targeting HTT transcripts for degradation have shown preclinical promise and will soon ent...

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Autores principales: Caron, Nicholas S, Southwell, Amber L, Brouwers, Cynthia C, Cengio, Louisa Dal, Xie, Yuanyun, Black, Hailey Findlay, Anderson, Lisa M, Ko, Seunghyun, Zhu, Xiang, van Deventer, Sander J, Evers, Melvin M, Konstantinova, Pavlina, Hayden, Michael R
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145682/
https://www.ncbi.nlm.nih.gov/pubmed/31745548
http://dx.doi.org/10.1093/nar/gkz976
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author Caron, Nicholas S
Southwell, Amber L
Brouwers, Cynthia C
Cengio, Louisa Dal
Xie, Yuanyun
Black, Hailey Findlay
Anderson, Lisa M
Ko, Seunghyun
Zhu, Xiang
van Deventer, Sander J
Evers, Melvin M
Konstantinova, Pavlina
Hayden, Michael R
author_facet Caron, Nicholas S
Southwell, Amber L
Brouwers, Cynthia C
Cengio, Louisa Dal
Xie, Yuanyun
Black, Hailey Findlay
Anderson, Lisa M
Ko, Seunghyun
Zhu, Xiang
van Deventer, Sander J
Evers, Melvin M
Konstantinova, Pavlina
Hayden, Michael R
author_sort Caron, Nicholas S
collection PubMed
description Huntington disease (HD) is a fatal neurodegenerative disease caused by a pathogenic expansion of a CAG repeat in the huntingtin (HTT) gene. There are no disease-modifying therapies for HD. Artificial microRNAs targeting HTT transcripts for degradation have shown preclinical promise and will soon enter human clinical trials. Here, we examine the tolerability and efficacy of non-selective HTT lowering with an AAV5 encoded miRNA targeting human HTT (AAV5-miHTT) in the humanized Hu128/21 mouse model of HD. We show that intrastriatal administration of AAV5-miHTT results in potent and sustained HTT suppression for at least 7 months post-injection. Importantly, non-selective suppression of huntingtin was generally tolerated, however high dose AAV5-miHTT did induce astrogliosis. We observed an improvement of select behavioural and modest neuropathological HD-like phenotypes in Hu128/21 mice, suggesting a potential therapeutic benefit of miRNA-mediated non-selective HTT lowering. Finally, we also observed that potent reduction of wild type HTT (wtHTT) in Hu21 control mice was tolerated up to 7 months post-injection but may induce impairment of motor coordination and striatal atrophy. Taken together, our data suggests that in the context of HD, the therapeutic benefits of mHTT reduction may outweigh the potentially detrimental effects of wtHTT loss following non-selective HTT lowering.
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spelling pubmed-71456822020-04-13 Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease Caron, Nicholas S Southwell, Amber L Brouwers, Cynthia C Cengio, Louisa Dal Xie, Yuanyun Black, Hailey Findlay Anderson, Lisa M Ko, Seunghyun Zhu, Xiang van Deventer, Sander J Evers, Melvin M Konstantinova, Pavlina Hayden, Michael R Nucleic Acids Res Chemical Biology and Nucleic Acid Chemistry Huntington disease (HD) is a fatal neurodegenerative disease caused by a pathogenic expansion of a CAG repeat in the huntingtin (HTT) gene. There are no disease-modifying therapies for HD. Artificial microRNAs targeting HTT transcripts for degradation have shown preclinical promise and will soon enter human clinical trials. Here, we examine the tolerability and efficacy of non-selective HTT lowering with an AAV5 encoded miRNA targeting human HTT (AAV5-miHTT) in the humanized Hu128/21 mouse model of HD. We show that intrastriatal administration of AAV5-miHTT results in potent and sustained HTT suppression for at least 7 months post-injection. Importantly, non-selective suppression of huntingtin was generally tolerated, however high dose AAV5-miHTT did induce astrogliosis. We observed an improvement of select behavioural and modest neuropathological HD-like phenotypes in Hu128/21 mice, suggesting a potential therapeutic benefit of miRNA-mediated non-selective HTT lowering. Finally, we also observed that potent reduction of wild type HTT (wtHTT) in Hu21 control mice was tolerated up to 7 months post-injection but may induce impairment of motor coordination and striatal atrophy. Taken together, our data suggests that in the context of HD, the therapeutic benefits of mHTT reduction may outweigh the potentially detrimental effects of wtHTT loss following non-selective HTT lowering. Oxford University Press 2020-01-10 2019-11-20 /pmc/articles/PMC7145682/ /pubmed/31745548 http://dx.doi.org/10.1093/nar/gkz976 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Chemical Biology and Nucleic Acid Chemistry
Caron, Nicholas S
Southwell, Amber L
Brouwers, Cynthia C
Cengio, Louisa Dal
Xie, Yuanyun
Black, Hailey Findlay
Anderson, Lisa M
Ko, Seunghyun
Zhu, Xiang
van Deventer, Sander J
Evers, Melvin M
Konstantinova, Pavlina
Hayden, Michael R
Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease
title Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease
title_full Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease
title_fullStr Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease
title_full_unstemmed Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease
title_short Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease
title_sort potent and sustained huntingtin lowering via aav5 encoding mirna preserves striatal volume and cognitive function in a humanized mouse model of huntington disease
topic Chemical Biology and Nucleic Acid Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145682/
https://www.ncbi.nlm.nih.gov/pubmed/31745548
http://dx.doi.org/10.1093/nar/gkz976
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