Remyelination Failure in Progressive MS: Grants Boost Efforts to Understand and Overcome It

Multiple sclerosis (MS) is a disease with two distinct phases, but only the first is currently treatable. Research carried out in the laboratory of Cleveland Clinic scientist Ranjan Dutta, PhD, may help change that — and has recently attracted two supportive grants to that end.

In about 85 percent of MS patients, disease onset is characterized by an immune-mediated relapsing/remitting phase, during which neurological disability occurs in cycles. Anti-inflammatory therapies aid in slowing the rate of relapses, but within 10 to 15 years approximately 85 percent of these patients move to the progressive phase of MS, for which anti-inflammatory therapy is no longer effective and no other treatments are currently available.

Now, with grants from the National MS Society and the National Institute of Neurological Disorders and Stroke (NINDS), Dr. Dutta and his team in the Department of Neurosciences in Cleveland Clinic’s Lerner Research Institute are conducting two studies focusing on the progressive phase of MS, with hopes of discovering underlying mechanisms and potential treatment targets.

“We hypothesize that there are two processes that occur in the early relapsing/remitting phase of the disease: a degenerative process and a repair process whose rate declines as the disease progresses,” says Dr. Dutta. “Ultimately, the disease reaches a threshold where the debilitated brain is unable to maintain the repair process to keep up with the progressive degeneration, resulting in permanent progressive disability. We have started to identify the mechanisms underlying both of these processes.”

Probing pathologic differences in primary and secondary progressive MS

In the first study, funded by a three-year, $460,000 grant from the National MS Society, Dr. Dutta and colleagues will investigate the differences between the 85 percent of MS patients with secondary progressive disease and the remaining 15 percent who have primary progressive disease and never experienced remissions.

The team will use a distinctive resource: brain tissues obtained from deceased patients through the rapid autopsy program of Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research. The tissues are from patients who presented with either primary or secondary progressive MS and had been monitored with MRIs and neurocognitive function testing for several years before they died. Tissues of patients with primary progressive disease will be studied to better understand how the absence of the initial immune-related disease phase alters genetic and cellular differences in various cortical regions that affect cell survival and cell death.

“We will identify pathways and molecules that differentiate patients with secondary progressive disease from those with primary progressive disease,” explains Dr. Dutta. “We hypothesize that there is an underlying axonal and neuronal degeneration accompanying the inflammatory demyelinating phase. We believe that understanding the complex interactions between these processes will elucidate the pathogenesis of disease and aid development of clinical therapies directed toward patients with progressive MS.”

He adds that the use of brain tissues collected through Cleveland Clinic’s autopsy program is a point of distinction: “Very few institutions in the world have a resource like this, so we are uniquely positioned to ask these critical questions associated with MS.”

Replicating human autopsy findings in animal models

The second grant, a five-year $1.7 million award from the NINDS, supports work that aims to further reveal factors influencing remyelination in MS. In this project Dr. Dutta and colleagues will reverse the conventional order of biomedical research by taking potential regulators of myelin repair identified in human autopsy tissues and attempting to replicate the results in animal models.

The team previously conducted a comprehensive analysis of MS white matter lesions and identified small, noncoding RNAs — known as microRNAs — that target genes associated with the maturation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes. The latter process is necessary for the remyelination that’s believed to fail in progressive MS. Now the team aims to validate these microRNAs and target genes in MS brains and animal models to determine whether the loss of microRNAs leads to decreased remyelination by halting the progression of OPC maturation into myelinating oligodendrocytes.

Figure. (Top left) Myelin immunostaining identifies a typical subpial MS lesion (loss of brown color) that extends from the surface of the brain to the deeper layers. These lesions, extensive in progressive MS brains, contribute to progressive neurologic disability. (Bottom left) Oligodendrocytes (myelin-making cells) and neurons present in the regions of nonlesioned gray matter (NLGM; normal myelin) and lesioned gray matter (LGM) will be compared to identify genes and other regulatory factors related to failure in remyelination and loss of neuronal function in progressive MS. (Right) Small regulatory RNAs that control gene expression are detected in cortical neurons in progressive MS brains (green cells; red is myelin).

End goal: A combinatorial treatment strategy

By characterizing failed myelin repair in MS brains, these studies should identify novel targets that will enhance repair of the MS brain, Dr. Dutta says.

“I think in the next few years we will have a better understanding of how the process of remyelination fails in MS,” he explains. “The future of MS therapeutics lies in identifying novel therapeutic targets against which combinatorial strategies can be developed that work in concert with current therapies but target the regenerative aspect.”

He notes that some remyelinating compounds are already in clinical trials. “Our research will provide a better understanding of how these drugs are working. Based on these outcomes, our research will prove to be even more important when the trial results are released.”