Until now, researchers studying multiple sclerosis (MS) in mouse models have relied on models heavily weighted towards processes secondary to an autoimmune trigger. While discoveries made through these models have informed later translational research and clinical trials to improve drug treatment for people living with MS, a lack of a model for the unique biological process by which the disease progresses in the brain has been challenging.

With the support of the National Multiple Sclerosis Society, a collaboration between Dr. Carles Vilarino-Guell, Dr. Jacqueline Quandt, Dr. Weihong Song, and Dr. Fabio Rossi has produced a model that is more likely to reflect the neurodegenerative and regenerative processes in the pathogenesis of progressive MS.

The team will characterize the molecular and behavioural properties of the disease model, and then look at the biological processes that are altered by a mutation associated with a familial form of MS.

“This is the first animal model of disease based on a genetic mutation linked to progressive MS,” explains Dr. Jacqueline Quandt, whose team developed one of the first models of MS based on human genetic risk factors in the early 2000s. “By bringing together our expertise in immune and neurodegenerative components in other models of MS, we are well poised to draw comparisons and more importantly employ some novel methods to explore and address mechanisms and plausible therapeutics most relevant to progressive MS.”

This effort builds on research that Dr. Vilarino-Guell published in 2016 that indicated a mutation in gene NR1H3, which is believed to be a major contributor to a progressive form of MS identified in two Canadian families. NR1H3 has been shown to regulate the production and proper folding of myelin, as well as inflammatory processes involved in damage and repair. The team aims to assess how disease develops and find novel treatment strategies to prevent disease onset and progression.

“Typically, MS model mice have carried an MS-like phenotype – the disease looks like MS – but now we have a model with a specific mutation that causes MS in patients, and may be able to look deeper at the biological causes of MS,” says Dr. Vilarino-Guell. “In order to fix what’s broken, you have to be able to see the cracks.”

Current treatments target the inflammatory and autoimmune responses triggered by MS, but the researchers believe that there is something going on earlier to produce the inflammation that results in demyelination in the brain. Myelin is a fatty substance that surrounds the nerve fibers of the brain and spinal cord, insulating the nerves and ensuring communication between different regions of the brain. In people with MS, the myelin deteriorates, making it harder for the brain to communicate with the body and which can result in cognitive and physical symptoms including loss of balance, impaired speech, extreme fatigue, double vision and paralysis.

For Dr. Vilarino-Guell, this new development is particularly exciting as he is hoping that it will accelerate research into a progressive genetic form of MS. Most patients have relapse-remitting MS and respond fairly well to treatment. However, the progressive, inherited form of MS can be more debilitating, and patients do not respond to the treatments currently available.

“This development is a real milestone for us, and one we hope will offer new opportunities to target the progressive disease and find better, more effective treatments for people living with MS,” says Dr. Vilarino-Guell.