Blocking SARM1 Prevents Neuronal Degeneration in Mice and Cell Models, Study Shows

Small molecule inhibitors that block the activity of SARM1 — an enzyme that plays a key role in nerve cell degeneration — prevent the degeneration of axons in mice and cellular models of disease, a preclinical study has found.

These findings may be the first steps towards the development of new targeted therapies for several neurodegenerative disorders, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and peripheral neuropathies.

The data were presented in the poster, “Small Molecule Inhibitors of SARM1 Prevent Axonal Degeneration in vitro and in vivo,” at the recent 2019 Society for Neuroscience Annual Meeting, in Chicago.

SARM1 is known to be one of the drivers of mechanisms that induce the degeneration of axons, extensions of nerve cells (also known as neurons) that are responsible for the transmission of the electrical signals within the central nervous system (comprising the brain and spinal cord).

Last year, investigators at Disarm Therapeutics presented a poster showing that blocking SARM1 activity protected axons from damage, and reduced the levels of two biomarkers of SARM1 activity and neurodegeneration — neurofilament light chain and cyclic ADP-ribose — in neurons cultured in a lab dish.

Now, they demonstrated that blocking the activity of SARM1 can protect axons from human and mice neurons cultured in a lab dish from different sources of damage, including mechanical, chemical, and mitochondrial damage.

“This is a breakthrough for Disarm and for patients affected by axonal degeneration,” Rajesh Devraj, PhD, chief scientific officer and founder of Disarm Therapeutics, said in a press release.

“We are moving rapidly to develop potent, orally active inhibitors of SARM1 to address the fundamental pathological process of axonal degeneration that drives disability progression in patients with diseases such as MS, ALS, and CIPN [chemotherapy-induced peripheral neuropathy],” Devraj said.

Moreover, they showed, for the first time, that inhibiting the activity of SARM1 using oral small molecule inhibitors can prevent the degeneration of axons, helping to maintain their normal structure and function in a mouse model of CIPN.

“Today’s findings are the first reported demonstration of pharmacologic SARM1 inhibition replicating the axonal protection we’ve previously described in genetic knockout models,” said Alvin Shih, MD, president and CEO of Disarm Therapeutics.

“SARM1 is the central driver of axonal degeneration, and today’s data further validate that it is an important and also druggable target. This marks significant progress in our development of oral SARM1 inhibitors,” Shih added.