Three cases of fibrodysplasia ossificans progressiva (FOP) a rare genetic disease, were reported recently in Stat’s health issue.
Wendy Weldon was a brave little nine years old when she first experienced a severe flare-up caused by a rare bone disease. An extra set of bones grew on her right arm freezing it at a 120-degree angle.
It was ten years later when Wendy went through the same experience with extra bones growing and freezing her left arm at a 180-degree angle. She was one year away from graduating high school but Wendy had to deal with the fact that there were many daily, ordinary activities that she would be unable to manage such as driving a car or even putting on a blouse by herself. Yet Wendy bravely prepared for college. Wendy is one of about eight hundred FOP cases worldwide.
Now at age 27, Wendy is looking for a job after completing her master’s in public relations. She has a full-time caregiver and mostly uses a wheelchair to get around New York’s busy streets. Wendy is hopeful that some of the new discoveries will eventually bring about a cure.
A simple explanation is that something goes wrong with the body’s healing process causing additional bone growth from connective tissue. Even a minor injury can cause inflammation and immobilize a joint or limb. As the patient ages, the bones will become rigid and impede gait, speech and even breathing.
For many years scientists were unable to explain the disease or develop a treatment. For more information on FOP please click here.
Two Doctor’s and Two Decades
In 1998 Dr. Kaplan encountered a little girl with symptoms. As he described it, seeing adults with the disease was difficult enough but seeing this little girl gave him some idea of the magnitude of the disease. Over the course of the next twenty years, he labored to find the genetic mutation that caused the disease.
In 1996 Dr. Aris Economides saw a photo of the skeleton of a deceased FOP patient in a scientific journal. He was immediately interested because he was researching proteins that drive bone growth. He became part of the FOP community. Dr. Economides firmly believes that the therapies now in clinical trials may finally save the lives of FOP patients.
A New Class of Drugs to Treat FOP
Researchers at Thomas Jefferson University discovered drugs originally developed to treat lung cancer could stop the growth of bones in mice. The mice were bred to simulate FOP’s characteristics.
The oral drugs had been already evaluated in clinical trials and proven safe so the licensing process and the repurposing to FOP could be expedited.
Clarissa Desjardins, a biotech scientist, was impressed with the work of the University researchers. She acquired the rights to the drugs through her newly formed company, Clementia Pharmaceuticals.
The two drugs take different molecular paths but both drugs halt new bone growth and prevent further devastating effects on the body.
The Cause and the Treatment
It has taken dedication by a group of FOP patients, researchers, and scientists to bring hope to the FOP community in the form of three medications that are now in human trials. In fact, there is a possibility that one medication may be approved by the FDA next year.
FOP is caused by a mutation to a gene called ALK-2 which becomes overactive and sets off interlocking proteins. This in turn creates cartilage that hardens into the extra sheaths of bone. Clementia’s drug, palovarotene, interferes with that process and targets a receptor critical to cartilage formation.
Patients who were treated with palovarotene in a short study evidenced about seventy percent less bone growth than those in the control group. A larger clinical trial that will test palovarotene taken every day has just begun. However, Clementia has received FDA approval based on previous data for use during flare-ups. The company will be submitting an application for approval in the near future.
The second drug, garetosmab, an antibody owned by Regeneron, blocks the mutant ALK-2 and prevents the bone flare-ups that cause the formation of additional bone. The scientists at Regeneron studied a molecular protein called Activin A that prevents ALK-2 from growing in in bones of healthy people. In FOP the opposite occurs. This prompted the scientists to work on a theory involving garetosmab that they are now testing in a worldwide global trial.
The third drug called BLU-782, owned by Blueprint Medicines is somewhat more advanced than the others in that it is selective of ALK-2. The intent is to stop ALK-2 before it binds to Activin A.
However, since it is almost an exact replica of other DNA genes it has been difficult to administer without interfering with normal processes. The good news is that the scientists were finally successful in creating a molecule that can be selective of ALK-2.
The International FOP Association (IFOPA)
The association began thirty years ago as an informal pen-pal group of parents and families related to FOP patients. Most of the money used for research at that time came from the group. It has since grown from the first eleven members into an international organization that has funded millions of dollars for research.
An offshoot of the search for a FOP cure came from a group of scientists at one of the international sessions. They discussed the fact that at times the bone growth that results from burns and breaks has the same molecular markers as FOP. This led to a joint effort by two doctors who are now working with Department of Defense-sponsored research to find out how this knowledge can help the injuries of combat veterans.
The doctors, scientists, and researchers all agree that once they see people with this condition they cannot just walk away.