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J Exp Med. 2019 Feb 4;216(2):294-303. doi: 10.1084/jem.20181040. Epub 2019 Jan 14.

Gene therapy targeting SARM1 blocks pathological axon degeneration in mice.

Author information

1
Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO.
2
Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MO.
3
Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MO.
4
Department of Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, MO diantonio@wustl.edu.
5
Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MO jmilbrandt@wustl.edu.

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.

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