Researchers Identify New Therapeutic Approach to Multiple Sclerosis With Sephin1

Treatments that protect oligodendrocytes could reduce the impact of multiple sclerosis (MS), according to a new study in mice published in the journal Brain.

Oligodendrocytes are cells that produce and maintain myelin, the protective sheath of fatty tissue that wraps around nerve fibers in the brain and spinal cord. MS damages these nerve fibers, and when that happens, the myelin sheath degenerates and nerve impulses slow down or stop.

The researchers studied mice suffering from a mouse model of MS and treated them with Sephin1 (selective inhibitor of a holophosphatase). They found that the loss of myelin and onset of debilitating disease were both postponed in mice who were treated with Sephin1.

Approximately 85% of patients with MS have relapsing-remitting disease, according to the National Multiple Sclerosis Society. In this form of the disease, patients experience episodes of acute worsening followed by remissions with partial or complete recovery. However, 60% to 70% of these patients eventually progress to secondary-progressive MS, in which there is a steady progression of symptoms and potential permanent neurological damage.

Sephin1 is a derivative of guanabenz (marketed as Wytensin), but it has fewer side effects. Guanabenz can cause drowsiness, weakness, headache, dry mouth, and even coma. Sephin1 boosts the integrated stress response, which protects endangered cells from inflammatory damage, and enhances p-eIF2α, a molecular signal that triggers a protective response against inflammatory damage.

Mice who were given Sephin1 showed a delay in the onset of clinical symptoms, reduced oligodendrocyte and axon loss, and diminished T-cell presence in the central nervous system.

“By protecting oligodendrocytes and diminishing demyelination we also reduce the generation of myelin debris,” senior study author Brian Popko, PhD, the Jack Miller Professor of Neurological Disorders and director of the Center for Peripheral Neuropathy at the University of Chicago, said in a statement. “The decreased exposure to myelin fragments should also limit the auto-immune response.”

The researchers also found that Sephin1 provided additional therapeutic benefits when used in combination with interferon β, a current first-line MS drug.

“Together, our results suggest that a neuroprotective treatment based on the enhancement of the integrated stress response would likely have significant therapeutic value for multiple sclerosis patients,” the authors concluded.

Reference

Chen Y, Podojil JR, Kunjamma RB, et al. Sephin1, which prolongs the integrated stress response, is a promising therapeutic for multiple sclerosis. Brain. 2019;142(2):344-361. doi: 10.1093/brain/awy322.