Drug Candidate Shows Promise in Reversing MS Nerve Damage in Mouse Model

Researchers have developed a drug that shows promise in animal models of multiple sclerosis (MS). If successful in humans, the drug could help to replace the protective insulation around nerve cells lost because of the disease.

The study is published in PNAS.

Drug development options for MS

MS is caused by degradation of a fatty coating called myelin that protects and insulates nerve cells. Loss of myelin affects the electrical impulses carried by nerve cells, exposing neurons like a bare wire, resulting in problems with movement, balance and vision.

There is no cure, but treatments can limit the progression of the disease. If left untreated, MS can lead to paralysis and shortened lifespan.

Researchers from the University of California San Francisco (UCSF) and Contineum Therapeutics have designed a drug to stimulate replacement of this lost myelin. If effective in humans, it could potentially curb or even reverse the progression of the disease.

“Ten years ago, we discovered one way that the body can regenerate its myelin in response to the right molecular signal, winding back the consequences of MS,” said Dr. Jonah Chan, a Debbie and Andy Rachleff Distinguished Professor of Neurology at UCSF and senior author of the study. “By carefully studying the biology of remyelination, we’ve developed a precise therapy to activate it – the first of a new class of MS therapies.”

A little help from snake venom

The new study builds on research from 2014, when Chan’s group screened over 1,000 drugs to identify a group of 8 compounds that may aid remyelination. They found the drugs prompted precursor cells to differentiate into myelin-producing cells called oligodendrocytes and stimulated remyelination.

These drugs – which included the antihistamine clemastine that showed the most promise – all acted by blocking muscarinic receptors, allowing the oligodendrocyte precursor cells (OPCs) to mature into oligodendrocytes.

However, a clinical trial led by Chan showed that clemastine only had a modest effect in patients with MS.

To have a more pronounced effect, they would have to take a more targeted approach. Analysis revealed clemastine blocks only one of the five muscarinic receptors – M1R – but this blocking effect was modest, and the drug also impacted other unrelated targets. This meant development of the ideal drug would need to be tailored specifically to M1R.

“Clemastine is not a targeted drug, affecting several different pathways in the body,” said Dr. Ari Green, chief of the Division of Neuroimmunology and Glial Biology in the UCSF Department of Neurology and co-author of the new study. “But from the get-go, we saw that its pharmacology with muscarinic receptors could point us toward the next generation of restorative therapies in MS.”

To reveal exactly where M1R was in the brain, researchers turned to an unlikely source: a toxin, MT7, found in the venom of the green mamba snake.

“We needed to prove, beyond doubt, that M1R was present in OPCs that were near the damage caused by MS,” said Dr. Michael Poon, a Contineum scientist and lead author of the study. “MT7, which is exquisitely selective for M1R, fit the bill.”

They used MT7 to engineer a molecular label for M1R that revealed rings of OPCs gathering around damage in both MS mouse models and human MS tissue.

These insights culminated in the development of PIPE-307, a compound that enters the brain to block M1R much better than clemastine in mouse models and prompted OPCs to mature into oligodendrocytes and begin myelinating nearby axons – reversing some of the degradation.

“A drug might seem to work in these abstract scenarios, affecting the right receptor or cell, but the key finding was actual recovery of nervous system function,” Chan said.

Two Phase 1 clinical trials have demonstrated the safety of PIPE-307 in humans, and the drug has now moved into a Phase 2 trial in MS patients.

“Every patient we diagnose with MS comes in with some degree of pre-existing injury,” Green said. “Now we might have a chance to not just stop their disease, but to also heal.”

Reference: Poon MM, Lorrain KI, Stebbins KJ, et al. Targeting the muscarinic M1 receptor with a selective, brain-penetrant antagonist to promote remyelination in multiple sclerosis. PNAS. 2024;121(32):e2407974121. doi: 10.1073/pnas.2407974121

This article is a rework of a press release issued by the University of California, San Francisco. Material has been edited for length and content.