Multiple Sclerosis

Posted on Multiple Sclerosis

“Can this new medication reverse the effects of multiple sclerosis?” And guess what it is helped by Green Mamba Venom

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.”

Posted on Multiple Sclerosis

“Can a stem cell transplant halt the progression of your multiple sclerosis?”

“In this video, I explore the topic of Hematopoietic Stem Cell Transplantation (HSCT) and its potential as a treatment for aggressive Multiple Sclerosis (MS). Specifically, I discuss autologous HSCT (aHSCT) and how it works by using a patient’s own stem cells to rebuild the immune system, which is often compromised in MS patients due to the immune system’s attack on the nervous system.”

Posted on Multiple Sclerosis

Can a computer tell patients how their multiple sclerosis will progress?

AI MS

Machine learning models can reliably inform clinicians about the disability progression of multiple sclerosis, according to a new study published this week in the open-access journal PLOS Digital Health by Edward De Brouwer of KU Leuven, Belgium, and colleagues.

Multiple sclerosis (MS) is a chronic progressive autoimmune disease that leads to severe disability over time through a complex pattern of progression, recovery, and relapse. Its global prevalence has increased by more than 30% over the last decade. Yet there are few tools that can predict the progression of MS to help clinicians and patients make life planning and treatment decision-making. 

In the new study, De Brouwer and colleagues used data on 15,240 adults with at least three years of MS history who were being treated at 146 MS centers in 40 countries. Data on two years of each patient’s disease progression was used to train state-of-the-art machine learning models to predict the probability of disease progression over the subsequent months and years. The models were trained and validated using strict clinical guidelines, promoting applicability of the models in clinical practice. While individual models varied in performance across different patient subgroups, the models had an average area under the ROC curve (ROC-AUC) of 0.71 ± 0.01. The study found that the history of disability progression was more predictive for future disability progression than treatment or relapse history.

The authors conclude that the models developed in the study have the potential to greatly enhance planning for individuals with MS and could be evaluated in a clinical impact study.

De Brouwer adds: “Using the clinical history of more than 15,000 people with multiple sclerosis, we trained a machine learning model capable of reliably predicting the probability of disability progression in the next two years. The model only uses routinely collected clinical variables, which makes it widely applicable. Our rigorous benchmarking and external validation support the vast potential of machine learning models for helping patients planning their lives and clinicians optimizing treatment strategies.”

Posted on Multiple Sclerosis

A new therapeutic target offers a promising pathway for multiple sclerosis treatment

Researchers find that blocking an overproduced channel protein could significantly improve symptoms in an animal model of multiple sclerosis.
Researchers find that blocking an overproduced channel protein could significantly improve symptoms in an animal model of multiple sclerosis.

Researchers from Kyushu University have identified a potential therapeutic target for the treatment of advanced multiple sclerosis (MS), a potentially disabling condition associated with the central nervous system. In their latest study, conducted using an experimental mouse model of MS, they explored the role of connexin 43 (Cx43), a protein involved in cellular communication and cardiac function, and examined whether targeting this protein with specific blockers could improve MS symptoms.

Like most neurodegenerative diseases, MS has very limited treatment options, more so once it reaches the chronic stage. To add to this, MS affects nearly three million people worldwide, making it a massively challenging neurological disease. Though our understanding of the precise nature of MS is limited, researchers have established that MS is caused by the patient’s own immune system wreaking havoc on their central nervous system. Specifically, the immune system attacks the protective myelin sheath surrounding nerve fibers in the brain and spinal cord, causing demyelination and creating areas of scarring and damage called lesions.

In a 2013 study, researchers from Kyushu University, including Associate Professor Ryo Yamasaki from the Faculty of Medical Sciences, found that the production of Cx43 was increased in supportive cells called astroglia, near chronic MS lesions. As mentioned earlier, Cx43 is essential for cell-to-cell signaling and plays a key role in modulating the immune system. The researchers therefore hypothesized that Cx43 could play a pivotal role in promoting neuroinflammation—a process where the immune response is triggered to fight off infection or heal damaged tissue—in the context of MS, ultimately leading to demyelination.

Now, a recent study published in Scientific Reports on May 13, 2024, by Yamasaki, in collaboration with researchers from the International University of Health and Welfare, adds further support to the hypothesis that Cx43 plays a key role in causing MS.  Their study has revealed that a drug called INI-0602, which effectively ‘plugs’ and blocks Cx43 channels, markedly improved MS symptoms in experimental mice.

The researchers conducted an extensive series of experiments in an experimental mouse model of MS and in cultured astroglia cells from the mouse model, to understand the effects of Cx43 blockade. The results of these tests and analyses were quite consistent, suggesting that INI-0602 could not only suppress the overproduction of Cx43 in astroglia, but also mitigate many of the hallmark features of MS, including demyelination and excessive immune cell infiltration into the nervous system.

By delving further into the mechanisms underlying these results, the team found that INI-0602 led to improved symptoms by regulating immune processes. More specifically, treatment with this compound reduced the levels of pro-inflammatory cytokines—proteins produced by immune cells that trigger the immune system—and increased those of anti-inflammatory cytokines in the cerebrospinal fluid. The drug also altered calcium signaling in astroglia, limiting their ability to promote inflammation. Together, these effects reduced disease severity in experimental mouse model. 

Overall, the findings of this study have important implications for future MS therapies. “Targeting Cx43 channels with specific blockers like INI-0602 could serve as a novel therapeutic strategy for chronic MS. This, in turn, could facilitate the development of new treatments for patients with MS,” highlights Yamasaki. He adds, “Our findings also challenge a critical issue in MS treatment, that of limiting disease progression in chronic stages by targeting Cx43, where current treatments are found to be less effective.”

Posted on Multiple Sclerosis

Neuroplasticity & Gut Health in Multiple Sclerosis

I found the following text: “How are gut health and neuroplasticity related in multiple sclerosis (MS)? More studies are shedding light on the significance of gut health and its impact on our physical and mental functions. Join me today as I interview Dr. Kim Bretz, ND. We discuss the role of neuroplasticity in gut disorders and she provides insight into what occurs in our gut when specific symptoms occur.”