How new gene discoveries could guide precision medicine in multiple sclerosis

Variants in three "complement" genes are closely associated with vision loss in multiple sclerosis, Johns Hopkins Medicine researchers discovered. (Pixabay)

The most severe form of multiple sclerosis, called progressive MS, causes the death of nerve cells, which often leads to vision loss and other neurological problems. Now, scientists at Johns Hopkins Medicine say they’ve identified gene variants that play a role in MS-related vision loss—a discovery that could help guide precision medicine for treating the disease as well as the development of new therapies, they believe.

The Johns Hopkins team tied vision loss in MS to three “complement system” genes, which make proteins that are normally associated with immune function. Using gene testing, advanced imaging and vision tests on MS patients over seven years, the researchers discovered that variants in the genes, called C1, CR1 and C1QA, were closely associated with vision loss. They published the findings in the journal Brain.

“We believe that our study opens up a new line of investigation targeting complement genes as a potential way to treat disease progression and nerve cell death,” said Peter Calabresi, M.D., professor of neurology and neuroscience and co-director of the Johns Hopkins Precision Medicine Center of Excellence for Multiple Sclerosis, in a statement.

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The team started by using optical coherence tomography to examine nerve cells in the retinas of 374 patients with MS. The scans allowed them to measure the thinning of the layer of those cells, which are known as ganglion cells, over time. Then they used blood samples from the patients to look for genetic mutations, pinpointing 23 variants in C3 in patients with the fastest rates of deterioration in ganglion cells.

A separate analysis of 835 patients who provided DNA samples and who underwent vision testing allowed the researchers to fine-tune their findings. They found that people with specific genetic variants in the complement gene C1QA were 71% more likely to lose their ability to detect visual contrasts over time, while those with changes in the CR1 gene faced a 40% risk of the same visual decline.

Several other research groups in MS are studying the role of genes and their variants in the progression and potential treatment of the disease. Early this year, a team at the University of Chicago found that a derivative of the hypertension drug Wytensin selectively inhibits a gene called PPP1R15A, which in turn seems to control inflammation in MS.

Scientists at the City University of New York and the Icahn School of Medicine at Mount Sinai focused in on Biogen’s MS blockbuster Tecfidera, shedding light on how the drug alters the gene expression of the immune system’s T cells. They believe their discoveries could inform the development of new MS therapies.

The next step for the Johns Hopkins researchers is to repeat their studies on MS-related vision loss in larger groups of patients. They’re also planning animal studies to help them figure out how the complement proteins work to destroy nerve cells in people with MS.

“From there we can possibly think about how to design new therapies,” said first author and assistant professor Kathryn Fitzgerald.