TY - JOUR
T1 - Gene therapy targeting SARM1 blocks pathological axon degeneration in mice
AU - Geisler, Stefanie
AU - Huang, Shay X.
AU - Strickland, Amy
AU - Doan, Ryan A.
AU - Summers, Daniel W.
AU - Mao, Xianrong
AU - Park, Jiwoong
AU - DiAntonio, Aaron
AU - Milbrandt, Jeffrey
N1 - Publisher Copyright:
© 2019 Geisler et al.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85061111385&partnerID=8YFLogxK
U2 - 10.1084/jem.20181040
DO - 10.1084/jem.20181040
M3 - Article
C2 - 30642945
AN - SCOPUS:85061111385
SN - 0022-1007
VL - 216
SP - 294
EP - 303
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 2
ER -