Updated Research Methods and Robust Treatment Pipeline Point to Hope on the Horizon for Progressive MS

In his update on progressive MS, Cleveland Clinic neurologist Robert J. Fox, MD, described features of relapsing MS (red) and progressive MS (green), emphasizing that these events occur in parallel, not as distinct phases.ORLANDO, Fla. – The lack of effective treatments for progressive forms of multiple sclerosis (MS) is still a major unmet need, despite a surge of collaborative research efforts in the past decade. In Monday’s Kurtzke Memorial Lecture at the Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, speaker Robert J. Fox, MD, presented the latest findings on progressive MS pathology and progress toward new therapies. Dr. Fox, who is staff neurologist at Cleveland Clinic’s Mellen Center for MS and Vice-Chair for Research at its Neurological Institute, is known for his work in progressive MS.

A recent shift in how progressive MS is characterized is based on an updated model of the MS clinical course proposed by Lublin and colleagues in 2020, Dr. Fox said. The newer model steps away from the well-known relapsing and progressive categories, but instead divides MS according to the presence or absence of active inflammation. “Active disease includes clinical relapses and evidence of inflammation on MRI,” he explained. “Somewhat separately, we have the accrual of disability that characterizes progressive disease. In contrast to what we once believed, these are not sequential stages, but are actually overlapping or parallel.” Making these distinctions even more difficult, a recent consensus statement concluded that reliable MRI indicators for either secondary progressive or primary progressive MS are still lacking.

To solve the mystery of progressive MS, we could search for clues in the behavior of cells that lead to the neurodegeneration, Dr. Fox suggested. New research is looking at the interplay between cell types such as astrocytes, microglia, and oligodendrocytes. “Astrocytes are specialized brain and spinal cord support cells which outnumber the neurons by as much as 10 to 1,” he said. These cells are thought to be influenced by environmental challenges, including dietary factors. Immune signals can also impact astrocytes, which can lead to cell death or further activation of the immune system.

Astrocytes, in turn, communicate with microglia (the resident immune cells within the brain) by exchanging various inflammatory molecules. These “conversations” can lead to stress that signals apoptosis or cell-programmed death. Astrocytes also carry on conversations with infiltrating T cells and natural killer cells, which may have some impact on progressive MS, Dr. Fox suggested. “Which cells are the true drivers of progressive MS? That will take more work to figure out.”

Identifying these drivers of MS progression may lead the way to new, targeted treatments. Dr. Fox presented a list of 27 agents that are currently under development for progressive MS, in addition to the approved relapsing MS therapies indicated in active secondary progressive disease. In the pipeline are several therapies in Phase 3 trials: two Bruton's tyrosine kinase (BTK) inhibitors, simvastatin, biotin (a negative trial), cladribine, and masinitib. Agents in the Phase 2 research stage include ibudilast, lipoic acid, domperidone, estriol, quetiapine, and several others.

What about stem cells? “This is probably the most commonly asked question we hear in the clinic,” Dr. Fox said. Mesenchymal stem cell research is of particular interest in progressive MS because of its potential to promote remyelination and repair. One path is to replace the stem cells in an effort to stimulate the brain’s native repair systems. Another pathway could involve pharmacological modulation of the endogenous stem cells—that is, introducing an agent that will promote repair by enhancing or “unblocking” the process by which oligodendrocyte precursor cells become mature oligodendrocytes. Novel research methods are looking at ways to test multiple pharmacologic agents at once to narrow down which ones might warrant further study.

With the robust pipeline and new ways of looking at this phase of the disease, hope for progressive MS is on the horizon, Dr. Fox concluded. He credited the collaborative activities of several organizations, including the CMSC, various MS registries, and the International Progressive MS Alliance which he is currently serving as co-President.