Seeking strategies to halt MS progression

Although great progress has been made in recent decades in the treatment of relapsing-remitting multiple sclerosis (MS), progressive MS remains poorly understood. The natural history of MS is notoriously variable; however, most patients eventually enter a progressive phase of the disease, resulting in ambulatory dysfunction that can be severe.

Researchers at Mayo Clinic are making significant advances in understanding the natural history and pathophysiology of MS, laying the groundwork for potential treatments. The goal is to slow or prevent the progressive phase of MS.

"The management of progressive MS remains frustrating, and progress is never fast enough for the people who are affected. But we are optimistic because developments are certainly moving in the right direction," says Dean M. Wingerchuk, M.D., a consultant in Neurology at Mayo Clinic in Phoenix/Scottsdale, Arizona.

Specific efforts include studies of factors affecting disease progression among diverse patients, as well as strategies for preventing axonal damage and thus halting progression. "Relapses contribute only about 2 percent of MS-related severe disabilities," notes Orhun H. Kantarci, M.D., a consultant in Neurology at Mayo Clinic in Rochester, Minnesota. "The remaining 98 percent happens with the progressive phase of the disease. None of the medications we have today impacts progression."

Early start of pathology

Previous studies have suggested that primary-progressive MS portended a worse prognosis than relapsing-remitting MS or secondary-progressive MS. However, in a study published in the Jan. 6, 2015, issue of Neurology, researchers at Mayo Clinic's campus in Minnesota showed that a clinical relapsing phase before the onset of progressive MS accelerates post-progression disability accumulation. Among patients studied, those with bout-onset progressive MS reached severe disability faster than did patients with primary-progressive MS.

"What happens after the first relapse, 15 or 20 years before progression starts, determines whether you're going to have progressive MS," Dr. Kantarci says. "If you don't repair well early on, whatever we might do to prevent relapses is not going to affect that one lesion in a critical location that can induce progression. Pathology is not a process that starts at the time when progressive MS starts."

In line with these findings, Mayo Clinic researchers are seeking greater understanding of radiologically isolated syndrome (RIS), in which intracranial abnormalities suggest MS in the absence of symptoms. Mayo Clinic is participating in an international study involving more than 500 patients in the U.S. and Europe, examining the feasibility of preventing the development of clinical MS in people with RIS. "We have to attack MS when it is crawling, not running," Dr. Kantarci says.

Focus on axons

Much of MS research and drug development has focused on demyelination. Medications that prevent or slow relapses generally target acute demyelinating events, either by blocking immune system access to the central nervous system or by reducing inflammation in that event.

"Those drugs can suppress relapses, but they've never prevented progression because axons are still being injured. We focus instead on trying to understand the factors injuring the axon, particularly immune-mediated effectors," says Charles L. Howe, Ph.D., director of the Translational Neuroimmunology Laboratory at Mayo Clinic's campus in Minnesota.

In research published in the November 2013 issue of Neurobiology of Disease, Dr. Howe and colleagues presented a novel model of immune-mediated axon injury involving cytotoxic CD8+ T lymphocytes. The model suggests strategies for targeted, early therapeutic intervention aimed at protecting axons and preventing irreversible loss of neurological function.

"We've discovered that there is a granzyme B-dependent pathway that is involved in this damage," Dr. Howe says. "Granzyme B is a protease that chews up very specific targets. It usually initiates an amplifying cascade of events that leads to cytotoxicity."

Current efforts involve identifying specifically anti-axonal pathogenic CD8+ T cells as well as studying the mechanisms by which they injure axons. "Most of the field has studied that in the context of killing cells," Dr. Howe says. "We're studying these events in an axon, where the events involve altering the cytoskeleton and the mitochondrial function of the axon, leading either to a run-down of energy that causes the axon to stop functioning, or to degradation of the cytoskeleton — which means the axon loses its physical integrity and is no longer able to make a connection."

Growing human neurons

In addition to animal models, the researchers have a chamber system that allows them to facilitate myelination of axons in vitro. "We've succeeded in getting myelin to regrow on axons from mice in a dish," Dr. Howe says. "Within two to three years, we will have human neurons growing in a dish with human oligodendrocytes added and putting myelin on axons."

Ultimately, Dr. Howe hopes to set up a biobank with fibroblasts from patients with MS that can be used to grow the patients' own neurons in the lab for individualized treatment. "We will then discover either that there is a common anti-axonal T cell that we can target globally across all MS patients or, perhaps more likely, we will find that each patient has his or her own unique anti-axonal T cell that we will have to design individual therapies to block," Dr. Howe says.

This individualized medicine approach offers great potential benefit for patients newly diagnosed with MS. "At the moment we're unable to predict with much confidence what will happen to any one individual," Dr. Wingerchuk says. "In the early stages of the disease, a patient wants to know, 'What's going to happen to me?' "

For more information

Paz Soldán MM, et al. Relapses and disability accumulation in progressive multiple sclerosis. Neurology. 2015;84:81.

Sauer BM, et al. Axons are injured by antigen-specific CD8-plus T cells through a MHC class I- and granzyme B-dependent mechanism. Neurobiology of Disease. 2013;59:194.