In 2006, Frederick Kaplan’s lab at the University of Pennsylvania pinpointed the inherited genetic mutation behind a horrifying disease that turns muscles, tendons, and ligaments into bone.
Until then, the only other people who really cared about fibrodysplasia ossificans progressiva (FOP) were the world’s few thousand patients and the families who watched them steadily become immobilized and die prematurely.
Now, Kaplan says, FOP is “a worldwide enterprise,” with several potential drugs in clinical testing and an explosion of interest among research universities and pharmaceutical companies.
“The FOP gene discovery launched an industry,” the professor of molecular orthopedic medicine wrote in the most recent annual report of Penn’s Center for Research in FOP and Related Disorders.
While FOP is ultra-rare, those related disorders are common. The FOP gene, called ACVR1, is crucial to the body’s development, growth, and repair. Understanding how it malfunctions in FOP has implications for treating a long list of serious bone problems – and much more. Indeed, Kaplan said the gene has recently been linked to digestive diseases and multiple sclerosis.
Last week, he sat in his office – his red tie covered with skeletons playing sports – at an opportune time for an FOP progress update. The Mutter Museum of the College of Physicians of Philadelphia on Thursday unveiled the skeleton of Carol Orzel, who became Kaplan’s first FOP patient in 1984. After she died last year, Kaplan helped fulfill her wish to join Harry Eastlack, who died in 1973 at age 39 of FOP, and whose skeleton is displayed at the museum.
Orzel knew that Kaplan made pilgrimages to the Mutter to study Eastlack’s ribbons, struts, and juts of bone, thereby forming or confirming hunches about living patients. She hoped her own body could be valuable in educating people about the disease.
But although Eastlack’s skeleton helped Kaplan see what FOP does, it was impossible to decipher the dysfunction at a molecular level until the FOP gene was identified.
Kaplan’s group and others — 37 research universities around the globe are now delving into FOP — have figured out that the mutation turns on the same bone-making pathway that is active during embryonic skeletal development and the healing of fractures. First, the pathway forms a cartilage scaffold, then transforms it into bone.
The result is normal bone – not just mineral deposits – in the wrong places. This “heterotopic ossification” can occur in people without the mutation in response to joint replacements, brain injury, spinal trauma, burns, and other conditions.
In FOP patients, this misplaced bone formation can be triggered even by minor injury or medical procedures. (Too often, doctors assume FOP is a cancerous tumor, so they do a biopsy — or worse — and unleash the disease.) Bone growth can also occur for still-unknown reasons during an FOP flare-up.
The good news is that the 2006 gene discovery revealed four molecular targets for potential drug therapies, and more have since been uncovered, according to the annual report of Penn’s FOP center.
The ultimate goal, Kaplan said, is to turn FOP into a manageable, chronic condition.
“I don’t think FOP is going to be any different in concept than common conditions like hypertension, asthma, or diabetes,” Kaplan said. “The more targets we have, and the more varied approaches we have, the more successful we’ll be at keeping the disease at bay and changing its natural course.”
Here are some leading therapeutic candidates:
Palovarotene: This drug, being developed by Canadian biotech company Clementia Pharmaceuticals, flips the off switch for cartilage formation. In mice, this approach was shown to tamp down misplaced bone growth. In 2016, the company announced encouraging results from a clinical trial of FOP patients, notably, a significant reduction in the volume of heterotopic bone made during flare-ups. A bigger, longer clinical trial is underway in 14 countries.
Activin A antibodies: In healthy people, activin A is a hormone-like protein that inhibits signals involved in bone formation. But studies revealed that in people with the FOP mutation, activin A has the opposite effect, driving bone growth. By chance, Tarrytown, N.Y.-based Regeneron Pharmaceuticals had a drug that blocked activin A sitting in its freezers, as Science magazine explained. With encouraging results from experiments in mice, Regeneron is now conducting a clinical trial of its drug, called garetosmab.
Imatinib: Kaplan calls inflammation the “ignition switch” that launches the “rocket” of FOP flare-ups. Imatinib, brand name Gleevec — a targeted cancer drug already approved for the treatment of chronic myeloid leukemia — suppresses certain inflammatory proteins involved in misplaced bone growth. Based on that biological connection, Kaplan’s group used imatinib to treat seven children with FOP who got no relief from standard anti-inflammatory drugs including corticosteroids. Imatinib reduced the intensity of their flare-ups. Kaplan’s group now urges a clinical trial — and discretionary use of imatinib to help children with uncontrolled flares.
For Kaplan, 67, the breakneck pace of discovery over the last 13 years is both heartening and heartbreaking.
“When we started this work, it was a wasteland. Now we’re at the watershed of clinical trials,” he said. “But the progress is never fast enough. I’ve had the anguish of seeing many children pass on.”
In 2010, four years after the discovery of the FOP gene, he had a personal health crisis. He suffered a stroke caused by bleeding in his brain. Scans revealed a cavernous hemangioma, a type of blood vessel malformation.
“The surgeons have said leave it alone,” he said. “It left me with some tremor, some imbalance. It gave me a new perspective on mortality. It makes me realize life is not forever.”
But his life’s work is unending.
“As long as I’m alive, I will always work on FOP,” he said. “I feel FOP research is currently on a trajectory to develop a therapy in our lifetime that will … change the natural history of the disease. And somewhere down the line, possibly even a cure, with a gene correction approach.”