Journal article
Gene therapy targeting SARM1 blocks pathological axon degeneration in mice
The Journal of experimental medicine, Vol.216(2), pp.294-303
02/04/2019
DOI: 10.1084/jem.20181040
PMCID: PMC6363435
PMID: 30642945
Abstract
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.
Details
- Title: Subtitle
- Gene therapy targeting SARM1 blocks pathological axon degeneration in mice
- Creators
- Stefanie Geisler - Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MOShay X Huang - Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MOAmy Strickland - Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MORyan A Doan - Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MODaniel W Summers - Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MOXianrong Mao - Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MOJiwoong Park - Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MOAaron DiAntonio - Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MOJeffrey Milbrandt - Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MO
- Resource Type
- Journal article
- Publication Details
- The Journal of experimental medicine, Vol.216(2), pp.294-303
- Publisher
- United States
- DOI
- 10.1084/jem.20181040
- PMID
- 30642945
- PMCID
- PMC6363435
- ISSN
- 0022-1007
- eISSN
- 1540-9538
- Grant note
- R01 NS087632 / NINDS NIH HHS K08 NS091448 / NINDS NIH HHS R01 CA218263 / NCI NIH HHS R01 CA219866 / NCI NIH HHS
- Language
- English
- Date published
- 02/04/2019
- Academic Unit
- Iowa Neuroscience Institute; Biology
- Record Identifier
- 9984070717102771
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