Axon Injury & Repair News

New strategy shows potential to block nerve loss in neurodegenerative diseases

Researchers at Washington University School of Medicine in St. Louis are working toward a treatment for neurodegenerative diseases that targets SARM1, a key molecule in the death of axons, the wiring of the nervous system. Shown, the axons (green) are thinner in a rodent model of an inherited axonal peripheral neuropathy (left). When SARM1 is missing from rodents with the disorder, the axons are thicker (right) and indistinguishable from normal, healthy axons. Finding ways to block SARM1 could lead to new therapies for a broad range of neurodegenerative diseases.

Two new studies from Washington University School of Medicine in St. Louis support development of a broadly applicable treatment for neurodegenerative diseases that targets a molecule that serves as the central executioner in the death of axons, the wiring of the nervous system.

Blocking this molecular executioner prevents axon loss, which has been implicated in many neurodegenerative diseases, from peripheral neuropathies to Parkinson’s disease, and glaucoma to amyotrophic lateral sclerosis (ALS).

The new studies, both published Oct. 26 in the Journal of Clinical Investigation, reveal surprising details about how the molecule — called SARM1 — triggers axon death that underlies the development of neurodegenerative diseases. The research also points to new therapeutic approaches for diseases defined by axon loss.

“We desperately need treatments for neurodegenerative diseases,” said co-senior author Jeffrey Milbrandt, MD, PhD, the James S. McDonnell Professor and head of the Department of Genetics. “With the evidence of SARM1’s central role in these diseases, we’re very interested in finding ways to block this molecule — whether with small molecule inhibitors or gene therapy techniques. Our latest research suggests we also may be able to interfere with its ability to drive damaging neuroinflammation. We’re hopeful this work will lead to effective new therapies across a range of neurodegenerative and neuroinflammatory diseases.”

In 2017, Milbrandt and co-senior author Aaron DiAntonio, MD, PhD, the Alan A. and Edith L. Wolff Professor of Developmental Biology, discovered that SARM1 is an enzyme that can promote neurodegeneration. Soon after, they co-founded a startup company called Disarm Therapeutics to boost the development of drug compounds that inhibit SARM1 for the treatment of diseases characterized by axon degeneration. In 2020, Disarm Therapeutics was acquired by Eli Lilly and Company to further the development of SARM1-targeted therapies for neurodegenerative diseases.

In healthy neurons, SARM1 is always switched off. But after injury or due to disease, SARM1 becomes active. Activated SARM1 is an arsonist — burning so much cellular energy that the axons can’t survive. This energy crisis triggers axons to disintegrate.

Read more at The Source.