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Gene therapy targeting SARM1 blocks pathological axon degeneration in mice
Axonal degeneration (AxD) following nerve injury, chemotherapy, and in several neurological disorders is an active process driven by SARM1, an injury-activated NADase. Axons of SARM1-null mice exhibit greatly delayed AxD after transection and in models of neurological disease, suggesting that inhibi...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363435/ https://www.ncbi.nlm.nih.gov/pubmed/30642945 http://dx.doi.org/10.1084/jem.20181040 |
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author | Geisler, Stefanie Huang, Shay X. Strickland, Amy Doan, Ryan A. Summers, Daniel W. Mao, Xianrong Park, Jiwoong DiAntonio, Aaron Milbrandt, Jeffrey |
author_facet | Geisler, Stefanie Huang, Shay X. Strickland, Amy Doan, Ryan A. Summers, Daniel W. Mao, Xianrong Park, Jiwoong DiAntonio, Aaron Milbrandt, Jeffrey |
author_sort | Geisler, Stefanie |
collection | PubMed |
description | Axonal degeneration (AxD) following nerve injury, chemotherapy, and in several neurological disorders is an active process driven by SARM1, an injury-activated NADase. Axons of SARM1-null mice exhibit greatly delayed AxD after transection and in models of neurological disease, suggesting that inhibiting SARM1 is a promising strategy to reduce pathological AxD. Unfortunately, no drugs exist to target SARM1. We, therefore, developed SARM1 dominant-negatives that potently block AxD in cellular models of axotomy and neuropathy. To assess efficacy in vivo, we used adeno-associated virus–mediated expression of the most potent SARM1 dominant-negative and nerve transection as a model of severe AxD. While axons of vehicle-treated mice degenerate rapidly, axons of mice expressing SARM1 dominant-negative can remain intact for >10 d after transection, similar to the protection observed in SARM1-null mice. We thus developed a novel in vivo gene therapeutic to block pathological axon degeneration by inhibiting SARM1, an approach that may be applied clinically to treat manifold neurodegenerative diseases characterized by axon loss. |
format | Online Article Text |
id | pubmed-6363435 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-63634352019-08-04 Gene therapy targeting SARM1 blocks pathological axon degeneration in mice Geisler, Stefanie Huang, Shay X. Strickland, Amy Doan, Ryan A. Summers, Daniel W. Mao, Xianrong Park, Jiwoong DiAntonio, Aaron Milbrandt, Jeffrey J Exp Med Research Articles Axonal degeneration (AxD) following nerve injury, chemotherapy, and in several neurological disorders is an active process driven by SARM1, an injury-activated NADase. Axons of SARM1-null mice exhibit greatly delayed AxD after transection and in models of neurological disease, suggesting that inhibiting SARM1 is a promising strategy to reduce pathological AxD. Unfortunately, no drugs exist to target SARM1. We, therefore, developed SARM1 dominant-negatives that potently block AxD in cellular models of axotomy and neuropathy. To assess efficacy in vivo, we used adeno-associated virus–mediated expression of the most potent SARM1 dominant-negative and nerve transection as a model of severe AxD. While axons of vehicle-treated mice degenerate rapidly, axons of mice expressing SARM1 dominant-negative can remain intact for >10 d after transection, similar to the protection observed in SARM1-null mice. We thus developed a novel in vivo gene therapeutic to block pathological axon degeneration by inhibiting SARM1, an approach that may be applied clinically to treat manifold neurodegenerative diseases characterized by axon loss. Rockefeller University Press 2019-02-04 /pmc/articles/PMC6363435/ /pubmed/30642945 http://dx.doi.org/10.1084/jem.20181040 Text en © 2019 Geisler et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles Geisler, Stefanie Huang, Shay X. Strickland, Amy Doan, Ryan A. Summers, Daniel W. Mao, Xianrong Park, Jiwoong DiAntonio, Aaron Milbrandt, Jeffrey Gene therapy targeting SARM1 blocks pathological axon degeneration in mice |
title | Gene therapy targeting SARM1 blocks pathological axon degeneration in mice |
title_full | Gene therapy targeting SARM1 blocks pathological axon degeneration in mice |
title_fullStr | Gene therapy targeting SARM1 blocks pathological axon degeneration in mice |
title_full_unstemmed | Gene therapy targeting SARM1 blocks pathological axon degeneration in mice |
title_short | Gene therapy targeting SARM1 blocks pathological axon degeneration in mice |
title_sort | gene therapy targeting sarm1 blocks pathological axon degeneration in mice |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363435/ https://www.ncbi.nlm.nih.gov/pubmed/30642945 http://dx.doi.org/10.1084/jem.20181040 |
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