Ten years of work and a little help from the green mamba snake have resulted in a promising new drug that is already being tested in clinical trials.
Multiple sclerosis (MS) deteriorates the protective insulation around nerve cells, causing their axons, which carry electrical impulses, to become exposed as bare wires. This can cause devastating problems with movement, balance and vision; and without treatment it can lead to paralysis, loss of independence and a shortened lifespan.
Now scientists from UC San Francisco and Contineum Therapeutics have developed a drug that prompts the body to replace the lost insulation called myelin. If it works in humans, it could be a way to reverse the damage caused by the disease.
The new therapy, called PIPE-307, targets an elusive receptor on certain cells in the brain, prompting them to mature into myelin-producing oligodendrocytes. Once the receptor is blocked, the oligodendrocytes spring into action and wrap around the axons to form 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, discovered this using a venom found in green mamba snake venom.
The work, which will be published on August 2 PNAScaps a decade of work by UCSF scientists Jonah Chan, PhD, and Ari Green, MD. Chan led the team to discover in 2014 that an obscure antihistamine known as clemastine could cause remyelination, which no one knew was possible.
Ten years ago, we discovered a way for the body to regenerate its myelin in response to the right molecular signal, reversing the effects of MS. By carefully studying the biology of remyelination, we have developed a precise therapy to activate it – the first of a new class of MS therapies.”
Jonah Chan, PhD, a Debbie and Andy Rachleff Distinguished Professor of Neurology at UCSF and senior author of the paper
A dirty medicine creates a clean opening
The original breakthrough came when Chan invented a method to screen drugs for their ability to cause remyelination. The research identified a group of drugs, including clemastine, that had one thing in common: they blocked the muscarinic receptors.
The benefits of Clemastine start with its effect on oligodendrocyte progenitor cells (OPCs). These cells remain dormant in the brain and spinal cord until they sense damaged tissue. They then move inward to form oligodendrocytes, which produce myelin.
For some reason, OPCs gather around decaying myelin during MS but fail to rebuild it. Chan found that clemastine activated OPCs by blocking muscarinic receptors, allowing the OPCs to mature into myelin-producing oligodendrocytes.
Nerves and their myelin are notoriously difficult to repair, whether due to MS, dementia or other injuries. Green and Chan conducted a trial of clemastine in patients with MS, and it was a success – the first time a drug demonstrated the ability to restore the myelin lost in MS. Despite being safe to use, clemastine was only modestly effective.
“Clemastine is not a targeted drug that affects different pathways in the body,” said Green, chief of the Division of Neuroimmunology and Glial Biology in the Department of Neurology at UCSF and co-author of the paper. “But from the beginning, we saw that its pharmacology with muscarinic receptors could point us to the next generation of restorative therapies in MS.”
A snake venom toxin illuminates the correct target
The researchers continued to use 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 clemastine’s benefits came from remyelination – and leading 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 moderate, and the drug also affected the other receptors. The ideal drug should target M1R.
At this point, the UCSF scientists needed an industrial partner to move the project forward. Ultimately, Contineum Therapeutics (then known as Pipeline Therapeutics) was founded to take a meticulous approach to creating that ideal drug. Chan and Green helped the company confirm that M1R was the right target for a remyelinating drug, and then create 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 located in the brain.
“We had to prove beyond a reasonable doubt that M1R was present in OPCs close to the damage caused by MS,” Poon said. “MT7, which is extremely selective for M1R, was a perfect fit.”
Poon used MT7 to develop a molecular tag for M1R that revealed rings of OPCs gathering around damage in a mouse model of MS and in human MS tissue.
Developing a drug that is ready for the clinic
A team of medicinal chemists at Contineum, led by Austin Chen, PhD, then went to work on the drug Chan and Green envisioned, designing PIPE-307 to powerfully block M1R and enter 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 and Green’s methods for monitoring remyelination. PIPE-307 blocked the M1R receptor much better than clemastine; caused OPCs to mature into oligodendrocytes and begin myelinating nearby axons; and it crossed the blood-brain barrier.
But most tellingly, it reversed the decline in a mouse model of MS.
“A drug may seem to work in these abstract scenarios and affect the right receptor or cell, but the key finding was the actual restoration 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 successful, it could change the way MS is treated.
“Every patient we diagnose with MS comes in with some degree of pre-existing injury,” Green said. “Now we may have a chance to not only stop their disease, but also cure it.”
Other authors include Kym I Lorrain, Karin J Stebbins, Geraldine C Edu, Alexander R Broadhead, Ariana J Lorenzana, Jeffrey R Roppe, Jill M Baccei, Christopher S Baccei and Daniel S Lorrain, all employees of Contineum Therapeutics.