Gene therapy targeting SARM1 blocks pathological axon degeneration in mice
Open accessAbstract
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.
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A transgenic mouse model overexpressing a dominant negative version of SARM1 in neurons showed a significant delay in axon degeneration.
“a transgenic mouse model overexpressing a dominant negative version of SARM1 in neurons showed a significant delay in axon degeneration”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [149]
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- Authors
- Geisler, S., Huang, S. X., Strickland, A., Doan, R. A., Summers, D. W., Mao, X., Park, J., DiAntonio, A., & Milbrandt, J.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Milbrandt, Jeffrey
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2019-01-14
- Volume
- 216
- Issue
- 2
- Pages
- 294-303
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC6363435
- OpenAlex
- W2910963998
- Cited by
- 145
- References
- 39
- Citations by year
- 2026: 8 · 2025: 24 · 2024: 13 · 2023: 15 · 2022: 29 · 2021: 26 · 2020: 19 · 2019: 11
- FWCI
- 10.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-sa)
- Funders
- National Institutes of Health (K08NS091448, R01CA219866, RO1NS087632, R01CA218263)
- Muscular Dystrophy Association (MDA344513)
- Thompson Family Foundation Initiative (PDS 155352)
- Hope Center Viral Vector Core
- Washington University School of Medicine in St. Louis
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- SARM1, axonal degeneration, gene therapy, adeno-associated virus, nerve transection, axotomy, neuropathy, NADase, axonal loss, neurodegenerative diseases, axon protection
- MeSH terms
- Dependovirus, Animals, Axons, Cytoskeletal Proteins, Disease Models, Animal, Humans, Mice, Transgenic, Nerve Degeneration, Transduction, Genetic, Genetic Therapy, Gene Targeting, Armadillo Domain Proteins, Mice, HEK293 Cells
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