Promising MS drug may make the debilitating disease worse

A drug that has shown promise for treating multiple sclerosis may actually make the debilitating disease worse, new research from the University of Virginia School of Medicine suggests.

The drug has not yet made it to human trials for MS, but the UVA scientists are warning their fellow researchers to proceed extremely cautiously. In addition to worsening the disease in mouse models, the drug also had unintended, off-target effects, they report.

It was not at all what we expected. The take-home message is that we should be very careful and do more fundamental research before we propose to take this to clinical trials."

Alban Gaultier, Ph.D., MS researcher of UVA's Department of Neuroscience and its Center for Brain Immunology and Glia (BIG)

About multiple sclerosis

Multiple sclerosis is a debilitating autoimmune disease that affects an estimated 1 million Americans. The disease causes the body's immune system to destroy myelin, the insulation that surrounds and protects our nerve fibers. This prevents the nerves from transmitting signals to the brain. The damage can create a wide range of symptoms, including muscle spasms, fatigue, difficulty moving, numbness and pain. These symptoms can vary from patient to patient.

Existing MS drugs carry unwanted side effects, such as impairing the body's ability to fight infections, so doctors are eager to develop better alternatives. One promising candidate is a small-molecule drug called TEPP-46. Originally developed to fight cancer, TEPP-46 targets what is known as "metabolic adaptation" - changes in how cells generate energy - that occurs in both cancer and MS.

In Gaultier's MS models, however, TEPP-46 worsened the disease, redirecting inflammation from the spinal cord into the brain. He and his collaborators determined the drug caused harmful changes in immune cells called T cells, though he and his team do not fully understand why. There were also unexpected "off-target" effects, meaning the drug affected other cellular processes than the one intended.

Gaultier notes his findings are at odds with other studies, and he says more research is needed before scientists move the drug into clinical trials in people with MS.

One upside to the new research is that it suggests that TEPP-46 could be used to create better mouse models of MS, helping scientists in their efforts to understand and treat the disease.

"It's something that could be very useful," Gaultier said. "In this animal model of MS, most of the inflammation takes places in the spinal cord. So by using that drug and reprogramming the immune cells, we were able to move the pathology from the spinal cord to the brain, which better mimics human disease."

Findings published

The researchers have published their findings in the scientific journal Science Signaling. The research team consisted of Scott M. Seki, Kacper Posyniak, Rebecca McCloud, Dorian A Rosen, Anthony Fernández-Castañeda, Rebecca M. Beiter, Vlad Serbulea, Sarah C. Nanziri, Nikolas Hayes, Charles Spivey, Lelisa Gemta, Timothy Bullock, Ku-Lung Hsu and Gaultier.

The research was supported by the Owens Family Foundation and the National Institutes of Health (NIH grants R01 NS083542, R33 MH108156, T32 GM008328, T32 GM007055, T32 GM007267, F31 NS103327 and NSF2018255830).