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

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.

Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that make up the lining of blood vessels — found in the umbilical cord of newborns.
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Inês Martins holds a BSc in Cell and Molecular Biology from Universidade Nova de Lisboa and is currently finishing her PhD in Biomedical Sciences at Universidade de Lisboa. Her work has been focused on blood vessels and their role in both hematopoiesis and cancer development.
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Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that make up the lining of blood vessels — found in the umbilical cord of newborns.
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5 comments

  1. EricALS says:

    Please speed up the process we need some better form of treatment. The time we have with the current drugs is a few extra months to live with severe disability!
    Is the only thing I will ever ask for while I’m on this Earth… I don’t need a new iPhone, I don’t need a Tesla car, I don’t need a faster processor… What we need is better treatment for serious diseases taking people every day from their families.

  2. Kenneth Jones says:

    I pray everyday for a breakthrough for treating ALS. My wife passed away this last June from ALS. Just a short comment, she was diagnosed in March 2018. Our President had just signed a law “Right to Try” where if there was a drug somewhere in the world and you were terminal you had a right to try. God does that sound logical? Well here was catch, Medicare would not pay for drug. If I did not have private insurance my wife would never had the monthly infusions.
    Want to thank all the people who are trying to do something to find a cure or treat this ugly disease which took my beautiful soulmate.

  3. Kenneth Jones says:

    I wrote a comment about my wife passing away from ALS this year and the fact that Medicare would not pay for the Radicava infusions and thankfully my private insurance did.
    For some reason my comments were not posted. Can someone have the courtesy of a response in why? Thankyou.

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