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news.The Myelin Repair Foundation (MRF), in partnership with the National Institutes of Health (NIH), announced today that patients are now being enrolled in a clinical trial conducted to study guanabenz, an FDA-approved drug to treat high blood pressure that was identified by MRF-funded researchers as a potential therapeutic to reduce loss of myelin, in multiple sclerosis (MS) patients.
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If successful, guanabenz (formerly called MRF-008) could be the first MS treatment to focus on protecting myelin from damage, which is the hallmark of MS, rather than on suppressing the immune system – as all currently available MS treatments do.
The trial, a collaboration between the MRF and the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (NIH) Clinical Center, is being led by NIH Investigators Dr. Irene Cortese, M.D., and Dr. Daniel Reich, M.D., Ph.D.
Myelin is the membrane sheath that surrounds and protects nerve fibers (axons) in the central nervous system, allowing for the quick and effective transmission of signals through the brain and spinal cord.
In MS patients, the immune system damages myelin and the cells that produce and maintain it (oligodendrocytes). As the disease progresses, severe myelin degeneration is accompanied by axonal loss and neurodegeneration, all of which can profoundly disrupt signaling in the central nervous system – leading to the array of symptoms that characterize MS.
Because loss of myelin correlates with neurodegeneration, new therapies that are designed to protect myelin or promote remyelination would be categorized as neuroprotective. MS is a chronic neurodegenerative disease, the most common disabling neurological disease of young adults, affecting 2.3 million people worldwide. The cause of MS is unknown.
In a Nature Communications paper published on March 13, 2015, MRF-funded researchers reported that guanabenz prevents myelin loss and alleviates clinical symptoms of MS in animal models by prolonging an innate mechanism that is activated in response to stressors such as inflammation.
When this protective response is disrupted or overloaded – by the chronic inflammation seen in MS, for example – oligodendrocyte cell death and demyelination are significantly enhanced. Treatment with guanabenz strengthens this stress-response mechanism and helps protect oligodendrocytes from cell death. These findings point to promising avenues for the development of new therapeutics against MS.
"Guanabenz appears to enhance the cell’s own protective machinery to diminish the loss of myelin," said senior study author Brian Popko, Ph.D., Jack Miller Professor of Neurological Disorders at the University of Chicago and a member of the Myelin Repair Foundation’s Research Consortium.
"While there have been many efforts to stimulate remyelination, this now represents a unique protective approach. You don’t have to repair the myelin if you don’t lose it in the first place."
The MRF has supported Dr. Popko’s research on the effects of inflammation on oligodendrocyte health and myelin production for over 10 years. In addition to Dr. Popko’s team at the University of Chicago, MRF-funded researchers at Northwestern University in Chicago, Case-Western Reserve University in Cleveland, and scientists at the MRF’s Translational Medicine Center in Sunnyvale, CA, made key contributions to the guanabenz publication.
The MRF’s clinical advisory board reviewed the preclinical data and encouraged the MRF to advance guanabenz into clinical testing. The drug’s protective efficacy and ability to alleviate myelin loss, coupled with its existing FDA approval and good safety profile, makes the clinical implications promising for MS patients, the advisory board concluded. However, before clinical studies could be initiated, the MRF had to identify a contract drug manufacturer to make clinical-grade guanabenz.
Because guanabenz has been off the market for many years, it is no longer manufactured anywhere in the world.
"We are very pleased that guanabenz is now moving into studies in MS patients," said Tassie Collins, Ph.D., Vice President of Translational Medicine at the Myelin Repair Foundation.
"This is a promising therapeutic approach, but it might not have been able to move forward without MRF’s participation." Because it is a generic drug, guanabenz would be an unlikely investment choice for pharmaceutical companies. And because it had to be custom-manufactured for the trial, most academic organizations would have been unable to resource it.