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An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion
Huntington’s Disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the huntingtin (HTT) gene. The mutant HTT (mHTT) protein causes neuronal dysfunction, causing progressive motor, cognitive and behavioral abnormalities. Current treatments...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8894458/ https://www.ncbi.nlm.nih.gov/pubmed/35241644 http://dx.doi.org/10.1038/s41467-022-28653-6 |
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author | Keller, Caroline Gubser Shin, Youngah Monteys, Alex Mas Renaud, Nicole Beibel, Martin Teider, Natalia Peters, Thomas Faller, Thomas St-Cyr, Sophie Knehr, Judith Roma, Guglielmo Reyes, Alejandro Hild, Marc Lukashev, Dmitriy Theil, Diethilde Dales, Natalie Cha, Jang-Ho Borowsky, Beth Dolmetsch, Ricardo Davidson, Beverly L. Sivasankaran, Rajeev |
author_facet | Keller, Caroline Gubser Shin, Youngah Monteys, Alex Mas Renaud, Nicole Beibel, Martin Teider, Natalia Peters, Thomas Faller, Thomas St-Cyr, Sophie Knehr, Judith Roma, Guglielmo Reyes, Alejandro Hild, Marc Lukashev, Dmitriy Theil, Diethilde Dales, Natalie Cha, Jang-Ho Borowsky, Beth Dolmetsch, Ricardo Davidson, Beverly L. Sivasankaran, Rajeev |
author_sort | Keller, Caroline Gubser |
collection | PubMed |
description | Huntington’s Disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the huntingtin (HTT) gene. The mutant HTT (mHTT) protein causes neuronal dysfunction, causing progressive motor, cognitive and behavioral abnormalities. Current treatments for HD only alleviate symptoms, but cerebral spinal fluid (CSF) or central nervous system (CNS) delivery of antisense oligonucleotides (ASOs) or virus vectors expressing RNA-induced silencing (RNAi) moieties designed to induce mHTT mRNA lowering have progressed to clinical trials. Here, we present an alternative disease modifying therapy the orally available, brain penetrant small molecule branaplam. By promoting inclusion of a pseudoexon in the primary transcript, branaplam lowers mHTT protein levels in HD patient cells, in an HD mouse model and in blood samples from Spinal Muscular Atrophy (SMA) Type I patients dosed orally for SMA (NCT02268552). Our work paves the way for evaluating branaplam’s utility as an HD therapy, leveraging small molecule splicing modulators to reduce expression of dominant disease genes by driving pseudoexon inclusion. |
format | Online Article Text |
id | pubmed-8894458 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-88944582022-03-17 An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion Keller, Caroline Gubser Shin, Youngah Monteys, Alex Mas Renaud, Nicole Beibel, Martin Teider, Natalia Peters, Thomas Faller, Thomas St-Cyr, Sophie Knehr, Judith Roma, Guglielmo Reyes, Alejandro Hild, Marc Lukashev, Dmitriy Theil, Diethilde Dales, Natalie Cha, Jang-Ho Borowsky, Beth Dolmetsch, Ricardo Davidson, Beverly L. Sivasankaran, Rajeev Nat Commun Article Huntington’s Disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the huntingtin (HTT) gene. The mutant HTT (mHTT) protein causes neuronal dysfunction, causing progressive motor, cognitive and behavioral abnormalities. Current treatments for HD only alleviate symptoms, but cerebral spinal fluid (CSF) or central nervous system (CNS) delivery of antisense oligonucleotides (ASOs) or virus vectors expressing RNA-induced silencing (RNAi) moieties designed to induce mHTT mRNA lowering have progressed to clinical trials. Here, we present an alternative disease modifying therapy the orally available, brain penetrant small molecule branaplam. By promoting inclusion of a pseudoexon in the primary transcript, branaplam lowers mHTT protein levels in HD patient cells, in an HD mouse model and in blood samples from Spinal Muscular Atrophy (SMA) Type I patients dosed orally for SMA (NCT02268552). Our work paves the way for evaluating branaplam’s utility as an HD therapy, leveraging small molecule splicing modulators to reduce expression of dominant disease genes by driving pseudoexon inclusion. Nature Publishing Group UK 2022-03-03 /pmc/articles/PMC8894458/ /pubmed/35241644 http://dx.doi.org/10.1038/s41467-022-28653-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Keller, Caroline Gubser Shin, Youngah Monteys, Alex Mas Renaud, Nicole Beibel, Martin Teider, Natalia Peters, Thomas Faller, Thomas St-Cyr, Sophie Knehr, Judith Roma, Guglielmo Reyes, Alejandro Hild, Marc Lukashev, Dmitriy Theil, Diethilde Dales, Natalie Cha, Jang-Ho Borowsky, Beth Dolmetsch, Ricardo Davidson, Beverly L. Sivasankaran, Rajeev An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion |
title | An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion |
title_full | An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion |
title_fullStr | An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion |
title_full_unstemmed | An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion |
title_short | An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion |
title_sort | orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8894458/ https://www.ncbi.nlm.nih.gov/pubmed/35241644 http://dx.doi.org/10.1038/s41467-022-28653-6 |
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