Regeneron Scientists Discover Key to Why Some People's Muscles Suddenly Turn into Bone

Regeneron Scientists Discover Key to Why Some People's Muscles Suddenly Turn into Bone
September 3, 2015
By Mark Terry, BioSpace.com Breaking News Staff

Tarrytown, N.Y.-based Regeneron Pharmaceuticals, Inc. announced yesterday that it had published a paper that described the discovery and preclinical validation of the primary mechanism that transforms muscles, ligaments and tendons in the rare disease, Fibrodysplasia Ossificans Progressiva (FOP). The article is published in the journal Science Translational Medicine.

FOP, also known as “stone man syndrome,” is caused by a mutation in the bone morphogenetic protein receptor ACVR1, which was believed to increase the receptor’s activity, which triggers inappropriate bone formation. This new research, however, suggests a different mechanism, with the mutation causing the ability to respond to activin, an injury-related factor.

The disease results in soft tissues actually turning into bone that can permanently freeze parts of the body, such as elbows or ankles, or the jaw or rib cage. About 97 percent of people with the disease have the same gene mutation. As Jennifer Couzin-Frankel writes in Science, “By sheer chance, Regeneron had a treatment for this particular target in its freezers. The company tested that potential therapy, a type of protein known as a monoclonal antibody, on mice with their own form of FOP and low and behold, they stopped growing unwelcome new bone.”

It’s not known whether the antibody will work on humans. Preclinical work is still being conducted. Although researchers had identified the genetic mutation in 2006, their understanding of the processes involved weren’t complete and presented a lot of questions.

The new work using mice models that had been manipulated into a type of FOP teased out a different explanation. In normal, healthy individuals, activin-A inhibits the ACVR1 receptors’ normal behavior, which controls bone growth. People with FOP have the opposite reaction to activin-A, which propels bone growth.

“Imagine you are driving your car down the road and you come to a red light,” said Aris Economides, executive director of Skeletal Diseases Therapeutic Focus Area and Genome Engineering Technologies at Regeneron to CBS News, “and you come to a red light. You press on the brakes and the car stops.” But, he continues, with FOP, “not only does your car not stop, actually the brakes are hot-wired to the accelerator.”

According to the U.S. National Institutes of Health (NIH), FOP affects one in every 2 million people worldwide. About 800 people are affected globally, according to the International FOP Association, with 285 in the U.S.

To date, treatment is prednisone, mostly to manage pain. Because actin is connected to injury and trauma, surgery exacerbates the disease. According to Econimides, cutting the excess bone spurs the excess bone development.

Regeneron utilized its proprietary VelociGene technology to create the mouse model of FOP, as well as its VelocImmune platform that allows the fast regeneration of fully human monoclonal antibodies. They were then able to generate and validate a possible therapeutic antibody that could selectively block Activin-A.

“We are excited and grateful to have this new fundamental insight into FOP,” said Betsy Bogard, global research development director of the International FOP Association (IFOPA) in a statement. “Regeneron’s extraordinary research findings bring new hope to the families who struggle with this devastating disease on a daily basis.

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