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Preclinical evaluation of WVE-004, aninvestigational stereopure oligonucleotide forthe treatment of C9orf72-associated ALS or FTD
A large hexanucleotide (G(4)C(2)) repeat expansion in the first intronic region of C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Several mechanisms have been proposed to explain how the repeat expansion drives disease, and we hypot...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9092894/ https://www.ncbi.nlm.nih.gov/pubmed/35592494 http://dx.doi.org/10.1016/j.omtn.2022.04.007 |
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author | Liu, Yuanjing Andreucci, Amy Iwamoto, Naoki Yin, Yuan Yang, Hailin Liu, Fangjun Bulychev, Alexey Hu, Xiao Shelley Lin, Xuena Lamore, Sarah Patil, Saurabh Mohapatra, Susovan Purcell-Estabrook, Erin Taborn, Kristin Dale, Elena Vargeese, Chandra |
author_facet | Liu, Yuanjing Andreucci, Amy Iwamoto, Naoki Yin, Yuan Yang, Hailin Liu, Fangjun Bulychev, Alexey Hu, Xiao Shelley Lin, Xuena Lamore, Sarah Patil, Saurabh Mohapatra, Susovan Purcell-Estabrook, Erin Taborn, Kristin Dale, Elena Vargeese, Chandra |
author_sort | Liu, Yuanjing |
collection | PubMed |
description | A large hexanucleotide (G(4)C(2)) repeat expansion in the first intronic region of C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Several mechanisms have been proposed to explain how the repeat expansion drives disease, and we hypothesize that a variant-selective approach, in which transcripts affected by the repeat expansion are preferentially decreased, has the potential to address most of them. We report a stereopure antisense oligonucleotide, WVE-004, that executes this variant-selective mechanism of action. WVE-004 dose-dependently and selectively reduces repeat-containing transcripts in patient-derived motor neurons carrying a C9orf72-repeat expansion, as well as in the spinal cord and cortex of C9 BAC transgenic mice. In mice, selective transcript knockdown was accompanied by substantial decreases in dipeptide-repeat proteins, which are pathological biomarkers associated with the repeat expansion, and by preservation of healthy C9orf72 protein expression. These in vivo effects were durable, persisting for at least 6 months. These data support the advancement of WVE-004 as an investigational stereopure antisense oligonucleotide targeting C9orf72 for the treatment of C9orf72-associated ALS or FTD. |
format | Online Article Text |
id | pubmed-9092894 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-90928942022-05-18 Preclinical evaluation of WVE-004, aninvestigational stereopure oligonucleotide forthe treatment of C9orf72-associated ALS or FTD Liu, Yuanjing Andreucci, Amy Iwamoto, Naoki Yin, Yuan Yang, Hailin Liu, Fangjun Bulychev, Alexey Hu, Xiao Shelley Lin, Xuena Lamore, Sarah Patil, Saurabh Mohapatra, Susovan Purcell-Estabrook, Erin Taborn, Kristin Dale, Elena Vargeese, Chandra Mol Ther Nucleic Acids Original Article A large hexanucleotide (G(4)C(2)) repeat expansion in the first intronic region of C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Several mechanisms have been proposed to explain how the repeat expansion drives disease, and we hypothesize that a variant-selective approach, in which transcripts affected by the repeat expansion are preferentially decreased, has the potential to address most of them. We report a stereopure antisense oligonucleotide, WVE-004, that executes this variant-selective mechanism of action. WVE-004 dose-dependently and selectively reduces repeat-containing transcripts in patient-derived motor neurons carrying a C9orf72-repeat expansion, as well as in the spinal cord and cortex of C9 BAC transgenic mice. In mice, selective transcript knockdown was accompanied by substantial decreases in dipeptide-repeat proteins, which are pathological biomarkers associated with the repeat expansion, and by preservation of healthy C9orf72 protein expression. These in vivo effects were durable, persisting for at least 6 months. These data support the advancement of WVE-004 as an investigational stereopure antisense oligonucleotide targeting C9orf72 for the treatment of C9orf72-associated ALS or FTD. American Society of Gene & Cell Therapy 2022-04-20 /pmc/articles/PMC9092894/ /pubmed/35592494 http://dx.doi.org/10.1016/j.omtn.2022.04.007 Text en © 2022 Wave Life Sciences https://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 | Original Article Liu, Yuanjing Andreucci, Amy Iwamoto, Naoki Yin, Yuan Yang, Hailin Liu, Fangjun Bulychev, Alexey Hu, Xiao Shelley Lin, Xuena Lamore, Sarah Patil, Saurabh Mohapatra, Susovan Purcell-Estabrook, Erin Taborn, Kristin Dale, Elena Vargeese, Chandra Preclinical evaluation of WVE-004, aninvestigational stereopure oligonucleotide forthe treatment of C9orf72-associated ALS or FTD |
title | Preclinical evaluation of WVE-004, aninvestigational stereopure oligonucleotide forthe treatment of C9orf72-associated ALS or FTD |
title_full | Preclinical evaluation of WVE-004, aninvestigational stereopure oligonucleotide forthe treatment of C9orf72-associated ALS or FTD |
title_fullStr | Preclinical evaluation of WVE-004, aninvestigational stereopure oligonucleotide forthe treatment of C9orf72-associated ALS or FTD |
title_full_unstemmed | Preclinical evaluation of WVE-004, aninvestigational stereopure oligonucleotide forthe treatment of C9orf72-associated ALS or FTD |
title_short | Preclinical evaluation of WVE-004, aninvestigational stereopure oligonucleotide forthe treatment of C9orf72-associated ALS or FTD |
title_sort | preclinical evaluation of wve-004, aninvestigational stereopure oligonucleotide forthe treatment of c9orf72-associated als or ftd |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9092894/ https://www.ncbi.nlm.nih.gov/pubmed/35592494 http://dx.doi.org/10.1016/j.omtn.2022.04.007 |
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