Although the mechanism of action of many multiple sclerosis treatments is unknown, scientists at Bad Nauheim’s Max Planck Institute for Heart and Lung Research and the University of Lübeck unlocked the mechanism for dimethyl fumarate (DMF), a multiple sclerosis drug that just received approval in Europe under the name Tecfidera. Dr. Nina Wettschureck’s and Dr. Markus Schwaninger’s research groups discovered the reason for immune function influence by DMF, which has also been used as a successful treatment for psoriasis.
Simply stated by Dr. Schwaninger, “In mice [with a standard model of multiple sclerosis] that don’t have the gene for the receptor called HCA2, DMF was unable to prevent the signs of paralysis.” Wild type mice with multiple sclerosis that were treated with DMF had significantly fewer problems with motor function, according to Dr. Wettschureck. In other words, DMF acts by blocking HCA2 receptor, a G protein-coupled membrane receptor found on the the surface of neutrophil granulocytes, a specific type of white blood cells. Activation of HCA2 receptor causes granulocytes to infiltrate the central nervous system, where auto-reactive immune cells damage neurons and cause multiple sclerosis. “Our study has enabled us to provide the first evidence that DMF’s protective effect is due to the HCA2 receptor. However, we are not ruling out the possibility that there may also be other mechanisms,” concluded Dr. Wettschureck.
“In animals treated with DMF, the number of granulocytes that infiltrated the nervous system was much lower than in untreated animals,” said Dr. Wettschureck, “In animals without the HCA2 receptor, the number of invasive granulocytes remained equally high despite treatment with DMF.” This suggests a reason for why patients respond differently to DMF and for how treatment may be custom-designed in the future: “It may be that individual genetic differences influence the efficacy of DMF,” stated Dr. Schwaninger.
To continue to improve treatments for multiple sclerosis, it may be beneficial to discover other agents that bind to HCA2 receptor. “Ideally, we would find a substance of comparable or even greater efficacy, but with fewer side effects,” said Dr. Wettschureck. DMF is an attractive multiple sclerosis drug because it can be taken in tablet form a has moderate side effects compared to other treatments such as glatiramer acetate and interferon beta medicines.