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A scientist and his zebrafish offer the best hope for a cure for a rare and disabling bone disease


By Nancy Humphrey
January 2011

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Greek mythology is rich with stories of gods and goddesses who suddenly and tragically turn to stone.

But for fewer than 3,000 people in the world, this mythological metamorphosis to stone is no Greek legend. A rare and disabling disorder, fibrodysplasia ossificans progressiva (FOP), happens episodically throughout life, replacing soft tissue like muscle and ligament with bone and, at its worst, turning bodies into living statues.

People with FOP basically form a second skeleton over existing bone that permanently locks parts of the body in place. About one in 2 million people are affected by the congenital disease that can remain dormant in the body until triggered by an injury or bumping or bruising of the body. Many patients with the disease have shortened lifespan when the growth of additional bone restricts breathing. Steroids help in some patients, but only minimally. Any attempt to remove the extra bone leads to the explosive growth of even more bone, only making the condition worse.

Hope for a treatment for the disabling disease rests squarely in the hands of a handful of physician scientists including Vanderbilt’s Charles Hong, M.D., Ph.D., an assistant professor of Medicine, Pharmacology and Cell and Developmental Biology, whose drug discovery research has uncovered a compound that could prevent the progression of this disabling disease.

“You wouldn’t wish FOP upon your worst enemy. It’s a horrible disease,” said the Harvard and MIT-educated Hong who had never heard of FOP until 2006.

Scientific Synergy
Sharon Kantanie of Brentwood, 41, was diagnosed with FOP when she was 6. Over the past 35 years most of her joints have been fused, but she is hopeful that new findings, including those from Hong, can help stop the progression in FOP patients, specifically in children who are just beginning their battle with the condition.

Sharon Kantanie. Photo by Daniel Dubois

Sharon Kantanie. Photo by Daniel Dubois

Although her Nashville home and Hong’s Preston Research Building lab are separated by only 12 miles, Hong and Kantanie first met in 2007. Her FOP physician, orthopaedic surgeon Fred Kaplan, M.D., of the University of Pennsylvania, one of the world’s leading authorities on the condition, put her in touch with Hong, shortly after he learned of the Vanderbilt physician scientist’s promising research.

The close-knit community of FOP patients and their families has long been included in frequent symposia about the disease and know many of the physicians and scientists working to unlock them from their prison of bone.

“This is a classic example of what academic research is all about,” Hong said. “I do basic science, so it’s very rare that my research has a chance to make a direct impact on somebody. This was my first experience where ordinary people wanted to visit my lab and really cared about our work. We almost see a finish line, and without raising false hope, we want to give it a full effort.”

In 2006, the FOP gene was discovered by Kaplan, Eileen Shore, M.D., and their colleagues at the University of Pennsylvania, and scientists found that the exact same mutation occurred in a bone-forming protein, the bone morphogenetic protein (BMP) receptor, in every FOP patient.

“It’s absolutely invariant,” Kaplan said. Children of an FOP parent have a 50 percent chance of inheriting the disorder, but it can’t be accurately detected during pregnancy screenings.

That same year, Hong and his colleagues at Harvard Medical School discovered a compound they named dorsomorphin that could inhibit all BMP receptors. Betting that chemicals that control signaling pathways in early development might also be useful as drugs to treat human diseases, Hong exposed zebrafish, a tiny freshwater fish used in drug discovery research, to thousands of different compounds and evaluated the embryos for changes in their body development.

They identified dorsomorphin, which made the embryo’s back-side (dorsal) structures more prominent, and also mimicked genetic changes to the BMP signaling pathway. Hong and his colleagues reasoned that the compound might act as an inhibitor of BMP signaling.

“We kind of stumbled into it, and through our discovery have made some really good friends who have treated FOP patients for years,” Hong said. “I’m new to this field, but our friends at the University of Pennsylvania have dedicated their entire careers trying to find the cause and a cure.”

Working Toward a Cure
Hong’s lab houses tanks of zebrafish, originally from the Ganges River in India. Zebrafish embryos are useful in understanding how all vertebrates, including people, develop from the moment that sperm fertilizes an egg. The eggs are clear and develop outside of the mother’s body allowing scientists to watch them grow into newly formed fish under a microscope.

A cardiologist with the Vanderbilt Heart and Vascular Institute, Hong studies chemicals that control how different parts of the body form at the precisely specified locations. When he found that dorsomporphin was an inhibitor of the gene involved in FOP, his research suddenly went in a very different direction.

“We could wait for drug companies to do it, but they aren’t going to spend a hundred million dollars on a disease that affects fewer than 3,000 people. It’s not cost effective for them. But that’s one of the great things about Vanderbilt. We have resources that other universities simply don’t. We can take full advantage of the drug discovery expertise of the Vanderbilt Institute of Chemical Biology, and make improved versions of dorsomorphin and test them on mice, with the ultimate hope of delivering these in the first trials for people with this disease in the next few years.”

Kaplan, who saw his first FOP patient in the 1980s, a decade after he entered practice, calls the condition “devastating” and is watching Hong’s research with interest.

“Nobody else is working on it. Nobody. And it’s the worst orthopaedic condition I have ever encountered,” said Kaplan, the Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine and Chief of the Division of Molecular Orthopaedic Medicine at the University of Pennsylvania School of Medicine. “Not everybody needs to be working on this, but someone does.”

Kaplan said that Hong’s research also holds promises for other conditions of heterotopic (extra) bone formation – for those with hip replacements, soldiers in Iraq injured by IEDs. “The 70 percent who survived have severe limb injuries and limited rehabilitation. Dr. Hong’s discovery very likely could have some utility for those people as well. The pathways are the same.”

Kaplan said the pediatric patients with the condition are particularly close to his heart. “The difference between seeing an adult and a child with this condition is like going to the World Trade Center site now versus Sept. 11 (2001). You see the hole in the ground now, and yes, it’s terrible, but you’re seeing the process after it’s complete. With children, you’re seeing the planes fly into the buildings. The catastrophe is happening right in front of your eyes.”

An unpredictable progression
Kantanie realizes that a treatment to stop the progression of FOP will be of little help to her since so many of her joints are locked into place, and any attempt to remove the extra bone simply triggers the growth of more bone.

“I think FOP research holds the most promise for children with FOP and their parents who hopefully won’t have to watch their children suffer the way my parents did,” Kantanie said.

Children with FOP appear normal at birth except for one telltale sign – their big toes are smaller than normal and turned inward. During the first or second decade of life, painful swelling that some physicians have mistaken for tumors, appear on the neck, back and shoulders, and turn into bone. The disease progression is unpredictable. In some, episodes, called flare-ups, occur frequently and close together. A joint can be frozen into place overnight. In others, it’s a gradual process.

Although Kantanie’s big toes were curved inward, her condition wasn’t diagnosed until she was 6 and woke up one morning with a bruised and swollen back. She was taken to a doctor in Chattanooga, where the family lived, and a biopsy of tissue was taken from under her arm. Her shoulders, neck and back fused into place after the biopsy.

“The diagnosis came fairly quickly, but my parents were told I’d be dead in a matter of a few years,” she said. Her parents searched for other opinions, and ended up at the Mayo Clinic. “The prognosis was much rosier there,” she said. Survival would be possible, but her parents were also told that her life would be full of unpredictable flare-ups.

After the initial fusing of her shoulder, her childhood was fairly free of flare-ups, until she turned 9 and her jaw fused after an injection of Novocain at the dentist’s office, followed by hip and knee problems in adolescence and restrictions in elbow movement in her late 20s.

Kaplan said FOP strikes both genders and all races equally. He knows of patients on every continent except Antarctica.

A skeleton of a man with fibrodysplasia ossificans progressiva, which forms a second skeleton over existing bone. (Courtesy New England Journal of Medicine.)

A skeleton of a man with fibrodysplasia ossificans progressiva, which forms a second skeleton over existing bone. (Courtesy New England Journal of Medicine.)

The way the disease progresses is particularly unfair to those who have it, he said. “Around the early teens, early 20s, right when a young person is ready to be independent, the hips usually become involved and walking becomes limited. Some people are actually stuck in a standing position. Life as we look at it becomes miserable.”

Despite the condition, Kaplan says most of his patients have a positive attitude about their lives. “It’s not the life they wanted, or had planned for, but they all have amazing outlooks. They seem to get over flare-ups and find meaning in life.”

Kantanie has used a wheelchair full-time since 2007, and is one of those who sees the glass half full. “When I was a child we didn’t know a lot about FOP. There’s still a lot we don’t know, but there’s a lot we do know. I try to tell parents of children with FOP that you don’t really know what life holds in store for your child, but there are people working on finding treatments, like Dr. Hong, so you have to hope for the best.”

Kaplan says that Hong’s research holds the “best hope.”

“If we can effectively and selectively block this pathway, we might turn
FOP from a catastrophic condition into something that’s only a minor inconvenience.”


 

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