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After years of suffering, new hope has emerged for patients. Multiple SclerosisScientists have come up with a promising treatment that could halt the progression of this chronic disease and repair the damage it causes. Ten years of work, and a little help from the green mamba, have led to the discovery of a promising new drug that is being tested on humans to treat multiple sclerosis.
Multiple Sclerosis
Multiple sclerosis (MS) is a chronic disease that affects the central nervous system. It is thought to be an autoimmune disorder, a condition in which the body mistakenly attacks itself. MS is an unpredictable disease that affects people in different ways. Some people with MS may have only mild symptoms. Others may lose their ability to see clearly, write, speak or walk, when communication between the brain and other parts of the body is disrupted.
Multiple sclerosis causes the deterioration of the protective insulating material that surrounds nerve cells, called myelin. Myelin is a protective sheath that surrounds nerves, like the insulation of electrical wires. When this sheath is damaged, the nerves' ability to transmit signals is affected.
Leaving the nerve axons that transmit electrical impulses exposed without the myelin sheath makes them like bare wires can cause devastating problems with movement, balance and vision. Left untreated, the disease can lead to paralysis, loss of independence and a shortened lifespan.
A drug that will change the course of multiple sclerosis treatment forever
Scientists at the University of California, San Francisco, and Continuum Therapeutics have developed a drug that prompts the body to replace the missing insulation. If successful in human trials, the drug could be a way to repair damage caused by the disease.
The new drug, called Pipe 307, works by activating certain cells in the brain that produce myelin, the protective sheath around nerves. This drug stimulates the cells to grow and multiply, which in turn repairs the damaged sheath and rebuilds the missing parts.
The work – which was published – is crowned Its results On July 31 in the journal PNAS – 10 years of work by UCSF scientists, including two Ph.D.s: Jonah Chan and Ari Green.
In 2014, Chan led a team of scientists to discover that a little-known antihistamine called clemastine could stimulate myelin regeneration, something no one knew was possible in the first place.
The team leader, a professor of neuroscience at the University of California, San Francisco, and the paper's lead author, said, according to the website: Youre Alert “Ten years ago, we discovered one way the body can regenerate myelin in response to the right signal, repairing what MS has broken. By carefully studying the biology of remyelination, we have developed a precision therapy that is the first of its kind in a new range of treatments for MS.”
Imprecise medicine offers opportunity to develop more precise medicines
Progress toward this discovery began when Chan invented a way to test the ability of drugs to initiate remyelination. The test identified a group of drugs, including clemastine, that all had one thing in common: they blocked muscarinic receptors.
The benefits of clemastine begin with its effect on cells that mature into oligodendrocytes. These cells remain dormant in the brain and spinal cord until they sense the presence of damaged tissue, then they move and transform into oligodendrocytes, which produce myelin.
Cells that could mature into oligodendrocytes cluster around the degraded myelin, but for some reason fail to rebuild it during MS. Chan discovered that clemastine works by blocking muscarinic receptors, allowing them to mature into myelin-producing oligodendrocytes.
Nerves and the myelin that protects them are difficult to repair once they are damaged, whether due to multiple sclerosis or dementia. Green and Chan tested clemastine in MS patients, and it worked. It was the first drug shown to restore myelin lost in MS. Although safe to use, clemastine had limited effectiveness.
“Clemastine is not a precision drug that targets a single receptor; it affects several different pathways in the body,” said Green, who is chair of neuroimmunology and glial cell biology in the UCSF Department of Neurology and a co-author of the paper. “But from the beginning, we saw that its action on muscarinic receptors could help us achieve the next generation of MS treatments.”
Snake venom reveals the right target
Researchers have continued to use clemastine to understand the therapeutic potential of myelin regeneration in MS. They have 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 come from remyelination.
The team found that clemastine's benefits came from blocking only one of the five muscarinic receptors, the M1 receptor, but its effect on it was moderate, and the drug also affected the other receptors. The ideal drug would need to focus on the M1 receptors.
Boone, a biologist at Continuum Therapeutics, realized that a toxin found in the deadly green mamba snake known as MT7 could reveal exactly where M1 receptors are located in the brain.
Bohn used MT7 to design a molecular marker for the presence of M1 receptors, which helped reveal rings of cells that can develop into oligodendrocytes clustering around damaged sites in a mouse model of MS and in human MS tissues worked on in the lab.
Clinical drug development
A team of medicinal chemists at Continuum Therapeutics, led by Dr. Austin, designed the drug Chan and Greene envisioned, coming up with the drug “Pipe 307,” which blocks M1 receptors.
In 2021, Pipe307 passed Phase I clinical trials, proving its safety. It is currently being tested in patients with multiple sclerosis in Phase II.
If successful, it could change how MS is treated. “Every patient we diagnose with MS comes with some degree of pre-existing damage, and now we may have a chance not only to stop the disease, but to cure it,” Green says.
