Target Molecule for Treatment of Multiple Sclerosis Identified

A protein marker expressed by a subset of human lymphocytes, which is capable of crossing the blood brain barrier and causing inflammation and damage to the neural tissues of individuals with multiple sclerosis (MS), has been singled out as a potential drug target for treatment of the disease.

Investigators at the University of Montreal (Canada) and their collaborators at the biotechnology company Prothena Corporation plc (Dublin, Ireland) have been studying MCAM (Melanoma Cell Adhesion Molecule), a 113,000-Dalton cell adhesion molecule.

They reported in the April 13, 2015, online edition of the journal Annals of Neurology that MCAM was expressed by human effector CD8+ T lymphocytes and was strikingly up-regulated during MS relapses. They demonstrated that MCAM+CD8+ T lymphocytes expressed more IL-17 (interleukin-17), IFN-gamma (interferon-gamma), GM-CSF (granulocyte-macrophage colony-stimulating factor) and TNF (tumor necrosis factor) than MCAM-negative lymphocytes, and exhibited an enhanced killing capacity towards oligodendrocytes. Blocking MCAM restricted the transmigration of CD8+ T lymphocytes across human blood-brain barrier endothelial cells in vitro. Blocking or depleting MCAM in vivo reduced chronic neurological damage in active, transfer, and spontaneous progressive animal MS models.

Research carried out by Prothena Corporation in the area of cell adhesion molecules has shown that MCAM functions like VELCRO hook-and-loop fasteners, allowing cells that express it to stick to the blood vessel wall and migrate into tissues to initiate their pathogenic process. For example, MCAM is expressed on pathogenic Th17-expressing immune cells that underlie inflammatory diseases and also is present on tumor cells involved in metastatic cancer. These insights have enabled the company to develop specific and novel antibodies that block MCAM’s VELCRO-like function and may have the ability to prevent disease-causing cells from spreading into tissue.

"We believe we have identified the first therapy that will impact the quality of life of people with multiple sclerosis by significantly reducing the disability and the disease's progression," said senior author Dr. Alexandre Prat, professor of neurosciences at the University of Montreal. "Our studies have shown that MCAM is necessary for the migration of CD4 and CD8 across the blood-brain barrier. If we block the interaction of MCAM with the protein to which it normally binds, we decrease the disease's activity. We observed a decrease of approximately 50% of the disease in mice with experimental autoimmune encephalomyelitis (EAE), the most widely used animal model of MS. What is especially significant is that we can stop the disease from the first symptoms in addition to having an impact on its progression, which is a first."

Related Links:
University of Montreal
Prothena Corporation plc