Multiple sclerosis (MS) is a disease that damages the protective insulation, called myelin, around nerve cells.
This leaves the nerve cells exposed, like bare wires, and can cause severe problems with movement, balance, and vision.
Without treatment, MS can lead to paralysis, loss of independence, and a shortened lifespan.
Now, scientists at UC San Francisco and Contineum Therapeutics have developed a drug called PIPE-307 that could help the body replace this lost myelin.
If it works in people, it could reverse the damage caused by MS.
How PIPE-307 works
The new therapy targets a specific receptor in the brain called M1R. When this receptor is blocked, certain cells in the brain, called oligodendrocytes, mature and start producing myelin again.
Oligodendrocytes wrap themselves around the nerve cells, forming a new myelin sheath.
Dr. Michael Poon, a scientist at Contineum, discovered that the M1R receptor is present on the cells that can repair damaged myelin. He used a toxin from green mamba snake venom to identify these receptors.
This research, published on August 2 in Proceedings of the National Academy of Sciences, is the result of a decade of work by UCSF scientists Jonah Chan, Ph.D., and Ari Green, MD. In 2014, Chan’s team discovered that an antihistamine called clemastine could induce remyelination, or myelin repair, which was previously thought impossible.
The journey to PIPE-307
Chan invented a method to screen drugs for their ability to promote remyelination. This screen identified clemastine as one of the drugs that blocked muscarinic receptors, which helped activate oligodendrocyte precursor cells (OPCs). These cells stay dormant until they sense injured tissue, then move in and become myelin-producing oligodendrocytes.
In MS, OPCs gather around damaged myelin but fail to repair it. Clemastine helped activate OPCs to mature into myelin-producing cells. Although clemastine showed some success in repairing myelin in MS patients, it was only modestly effective because it was not a targeted drug.
Green and Chan realized that a more targeted drug, one that specifically blocked the M1R receptor, could be more effective. Contineum Therapeutics was formed to develop such a drug. Using MT7, a toxin from green mamba snake venom, Poon and his team proved that M1R was present in OPCs near the damaged myelin.
A team of medicinal chemists at Contineum, led by Dr. Austin Chen, designed PIPE-307 to block M1R effectively and enter the brain. Tests on OPCs in petri dishes and animal models of MS showed that PIPE-307 worked better than clemastine. It prompted OPCs to mature into myelin-producing cells and repair the damaged myelin.
In 2021, PIPE-307 passed a Phase I clinical trial, proving its safety. It is now being tested in MS patients in Phase II trials.
If successful, PIPE-307 could transform MS treatment by not only stopping the disease but also healing the damage it causes. “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.”
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