Genetic Research Reveals Possible New Targets For Treatment Of Myasthenia Gravis October 15, 2015 Smith

NEW YORK – A new genome-wide association study suggests that immunomodulating drugs already approved by the U.S. Food and Drug Administration (FDA) could benefit patients with myasthenia gravis.

Dr. Bryan Traynor, chief of the Neuromuscular Diseases Research Section at the National Institutes of Health in Bethesda, Maryland, and colleagues, found three different disease-associated loci in myasthenia gravis patients. One locus was at CTLA4, and the FDA has approved two CTLA4-targeting treatments, abatacept and belatacept, for treating rheumatoid arthritis and renal transplant patients, respectively.

The findings also showed two distinct, but overlapping, disease-associated loci for the early- and late-onset forms of the illness
 

“The discovery of a genetic locus is always an exciting thing, but often times it can take 10 to 15 years between the discovery of a particular locus and a first-in-humans clinical trial,” Dr. Traynor told Reuters Health in a telephone interview. The fact that drugs targeting CTLA4 are already FDA approved should accelerate that timeline, he added.

In their study, published online February 2 in JAMA Neurology, Dr. Traynor and his colleagues looked at DNA from more than 1,000 white, North American patients with acetylcholine-receptor antibody positive myasthenia gravis and nearly 2,000 controls.

They investigated associations between more than 8 million variants and myasthenia gravis risk. Significant association signals were found at CTLA4 (odds ratio, 1.37); HLA-DQA1 (OR, 2.31) and TNFRSF11A (OR, 1.31).

The CTLA4 and HLA-DQA1 associations were replicated in a cohort of 423 myasthenia gravis patients and 467 controls from Italy.

The analysis also confirmed past observations that myasthenia gravis strikes younger patients, who are usually female, as well as patients 60 and older who are usually male.

We were able to find different genetic loci that drive genetic susceptibility in each case,” Dr. Traynor said. “We genetically proved that they are two fundamentally different conditions, but overlapping conditions as well.”

The CTLA4 associations were seen in both early- and late-onset patients, the researcher noted. It’s likely, he added, that clinical trials testing CTLA4-targeting drugs in myasthenia gravis would enroll all patients with the illness, regardless of their genotype.

Even in patients who don’t have the CTLA4 variants he and his colleagues identified, Dr. Traynor noted, “it’s possible that in the other patients there are other variants in that region that are altering CTLA4 function, but we are not powered to pick it up.”

While effective therapy for myasthenia gravis is available, the researcher added, some patients with the disease do wind up having significant problems. “I think there is considerable room to grow new treatments,” Dr. Traynor said.

Dr. Robert Lisak of Wayne State University School of Medicine in Detroit co-authored an editorial accompanying the study.

“As in other complex immune-mediated disorders, there is an important influence of minor changes in multiple genes, likely interacting with the environment and with one another and their protein products, in the pathogenesis of myasthenia gravis,” Dr. Lisak told Reuters Health by email. “And in an autoimmune disease it is not surprising that the minor changes occur in genes for proteins that are critical in the immune response.”

“Identifying changes in genes in patients with different types of myasthenia gravis has the potential to help us understand which molecules and pathways in the immune system are the most important in development of disease,” he added. “In theory that might help in development of more-focused treatments for patients with myasthenia gravis. Only time will tell if this ultimately happens.”