Some rare diseases pull researchers in and don’t let them go, and the unusual bone condition called fibrodysplasia ossificans progressiva (FOP) has long had its hooks in Aris Economides. “The minute you experience it it’s impossible to step back and forget it,” says the functional geneticist who runs the skeletal disease program at Regeneron Pharmaceuticals in Tarrytown, New York. “It’s devastating in the most profound way.”
The few thousand or so people with FOP worldwide live with grueling uncertainty: Some of their muscles or other soft tissues periodically, and abruptly, transform into new bone that permanently immobilizes parts of their bodies. Joints such as elbows or ankles may become frozen in place; jaw motion can be impeded and the rib cage fixed, making eating or even breathing difficult.
Twenty years after he first stumbled on FOP, Economides and his colleagues report today that the gene mutation shared by 97% of people with the disease can trigger its symptoms in a manner different than had been assumed—through a single molecule not previously eyed as a suspect. And 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 lo and behold, they stopped growing unwelcome new bone.
Whether the antibody will work in people remains uncertain. Regeneron is continuing to test it and hopes to advance to clinical trials when ready. Researchers who study the disorder are welcoming the company’s new insight. “I was really surprised” that the defective gene behaves this way, says Eileen Shore of the University of Pennsylvania, a geneticist and cell and molecular biologist who was instrumental in discovering the FOP gene back in 2006 (Science, 28 April 2006, p. 514). “Everyone I know of that I’ve talked to is surprised.”
Economides first learned about FOP back in 1996, just after finishing a postdoctoral fellowship at Regeneron, then a young biotech company focused on neurological disorders. Researchers there were studying a protein in animals and realized that it might stop the buildup of bone, which led them to learn about FOP. Although that protein didn’t progress to a drug, Economides was struck by a picture he happened upon of Harry Eastlack, a FOP patient who had donated his skeleton, with its many extra layers of bone growth, to the Mütter Museum in Philadelphia, Pennsylvania. Economides met some people with FOP, and their stories stayed with him though he temporarily left FOP research behind.
In 2006, researchers discovered the genetic defect behind FOP: A mutated version of the gene ACVR1, which in patients produces an overactive form of a cell surface protein called a transmembrane receptor. The normal version of the receptor responds to its natural partner molecule, called a ligand, by sending signals into cells that spur bone to grow.
But Economides remained puzzled about how exactly the defective gene was causing such striking bone growth in FOP. In 2012, Regeneron took on that mystery. One question was whether the mutated ACVR1 receptor in FOP needed the ligand to trigger excess bone growth, or whether the receptor’s modest, perpetual activity could trigger new bone on its own. To find out, he and his colleagues gave FOP mice a drug that blocked that ligand-receptor interaction. The mice stayed largely healthy, suggesting that the ligand was necessary for excess bone to form.
But now Economides had another puzzle on his hands. There are many potential ligands for this particular receptor, and although he’d blocked them all in the mice, he couldn’t do that in a person without potentially interfering with vital signaling pathways that could produce myriad serious side effects. He needed to get more specific. Which ligand was the culprit? In studies of cells, the team was surprised to learn that a family of ligands they had never considered as relevant to FOP, called activins, were switching on the mutant form of ACVR1; activins typically curb signaling by the normal receptor.
Another clue came from the work of Frederick Kaplan at the University of Pennsylvania, an orthopedic surgeon and FOP pioneer who has been studying the disease for years, and who helped lead the team that found the FOP gene. Kaplan’s research suggested that FOP had an inflammatory component—and, as it happened, one of the activin ligands, called activin A, was involved in inflammation.
These pieces added up to the following scenario. In healthy people, activin A inhibits the normal ACVR1 receptor, keeping bone growth under control. But in people with FOP, the new experiments suggest, activin A has the opposite effect on the mutant receptor, driving bone growth. The work is published today in Science Translational Medicine.
The pieces fit together for another reason: It has long been known that FOP patients are more likely to grow bone after they sustain an injury, even just a minor one such as tripping over something left on the floor. Activin A is generated after exactly these sorts of bumps—the protein is churned out by immune cells when there is an injury. “We knew injury was a part of it, but we didn’t know what injury did to change” the body so that bone growth resulted, says Paul Yu, who studies FOP at Brigham and Women’s Hospital in Boston and is a co-author on the new paper.
There remains much debate about whether an antibody blocking activin A, which is what Regeneron had stored in its freezers and tested on its mice, will work in FOP patients. “We don’t know yet the significance of this for humans,” Kaplan cautions. He is now trying to verify the findings in cells from FOP patients and healthy people.