Ten years of effort, along with assistance from the green mamba snake, have led to the development of a promising new drug that is currently undergoing clinical trials.

Multiple sclerosis (MS) damages the protective insulation around nerve cells, leaving their axons, which carry electrical impulses, exposed like bare wires. This can lead to serious issues with movement, balance, and vision. Without treatment, it can result in paralysis, loss of independence, and a reduced lifespan.

Researchers at UC San Francisco have created a medication that stimulates the body to regenerate myelin, the protective insulation around nerves. If successful in human trials, this drug could potentially reverse the damage caused by the disease.

The new therapy, known as PIPE-307, focuses on a hard-to-find receptor on specific brain cells. This receptor triggers the maturation of these cells into myelin-producing oligodendrocytes. When the receptor is blocked, the oligodendrocytes become active, wrapping around the axons to create a new myelin sheath.

It was crucial to prove that the receptor, known as M1R, was present on the cells that can repair damaged fibers. Contineum scientist and first author Michael Poon, PhD, figured this out using a toxin found in green mamba snake venom. 

The work, which was published on Aug. 2 in PNAS, marks the culmination of a decade of research by UCSF scientists Dr. Jonah Chan and Dr. Ari Green. In 2014, Dr. Chan led the team and made a groundbreaking discovery that an overlooked antihistamine called clemastine could stimulate remyelination, a process that was previously thought to be impossible.

“Ten years ago, we discovered a way that the body can regenerate its myelin in response to the right molecular signal, reversing the effects of MS,” said Chan, a Debbie and Andy Rachleff Distinguished Professor of Neurology at UCSF and senior author of the paper. “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 dirty drug creates a clean opening.

The original breakthrough happened when Chan developed a method to screen drugs for their ability to promote remyelination. The screening uncovered a group of drugs, including clemastine, all sharing a common trait: they blocked muscarinic receptors.

Clemastine’s benefits begin with its impact on oligodendrocyte precursor cells (OPCs). These cells remain dormant in the brain and spinal cord until they sense injured tissue. Then, they migrate and give rise to oligodendrocytes, which produce myelin.

“In multiple sclerosis (MS), oligodendrocyte precursor cells (OPCs) tend to gather around deteriorating myelin but are unable to regenerate it. Chan found that clemastine stimulates OPCs by blocking muscarinic receptors, which enables the OPCs to develop into myelin-producing oligodendrocytes.”

Nerves and their myelin are very difficult to repair, whether due to conditions like MS, dementia, or other injuries. Green and Chan conducted a successful trial of clemastine in MS patients, marking the first time a drug showed the ability to restore lost myelin in MS. Although clemastine was deemed safe to use, its effectiveness was only moderate.

“Clemastine is not a targeted drug; it affects several different pathways in the body,” said Green, Chief of the Division of Neuroimmunology and Glial Biology in the UCSF Department of Neurology, and co-author of the paper. “But from the beginning, we recognized that its pharmacology with muscarinic receptors could guide us towards the development of the next generation of restorative therapies in MS.”

A snake venom toxin illuminates the right target

The researchers continued using clemastine to understand the curative potential of regenerating myelin in MS. They developed a series of tools to monitor remyelination, both in animal models of MS and in MS patients, showing that the benefits seen with clemastine came from remyelination – and pointing the way for how new drugs should be tested and evaluated.

They also found that clemastine’s benefits came from blocking just one of the five muscarinic receptors, M1R, but the effect on M1R was middling, and the drug also affected the other receptors. The ideal drug would need to zero in on M1R.

The scientists at UCSF needed a partner from the industry to move the project forward. Eventually, Contineum Therapeutics (formerly known as Pipeline Therapeutics) was established with the goal of developing an ideal drug through a meticulous approach. Chan and Green played a key role in confirming that M1R was the correct target for a remyelinating drug and then creating a drug that exclusively blocked it.

Poon, a biologist at Contineum, realized that MT7, a toxin found in the venom of the deadly green mamba snake, could reveal exactly where M1R was in the brain.

“We needed to prove, beyond doubt, that M1R was present in OPCs that were near the damage caused by MS,” Poon said. “MT7, which is exquisitely selective for M1R, fit the bill.”

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

Developing a clinic-ready drug

A team of medicinal chemists at Contineum, led by Austin Chen, PhD, then got to work on the drug that Chan and Green envisioned, designing PIPE-307 to potently block M1R and get into the brain.

The researchers tested the effects of the new drug on OPCs grown in petri dishes and the animal models of MS using Chan’s and Green’s methods for tracking remyelination. PIPE-307 blocked the M1R receptor much better than clemastine; prompted OPCs to mature into oligodendrocytes and begin myelinating nearby axons; and it crossed the blood-brain barrier.

But most tellingly, it reversed the degradation seen in a mouse model of MS.

“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. 

In 2021, PIPE-307 passed a Phase I clinical trial, demonstrating its safety. It is currently being tested in MS patients in Phase II. 

If it succeeds, it could transform how MS is treated. 

“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.”