It's not a common disease.  But it is a devastating, merciless one, even more so because most of its victims are children. Fibrodysplasia ossificans progressiva (FOP) sounds like something from a warped horror movie, but it is all too real: a genetic condition in which muscle turns to bone in episodic flare-ups with cumulative life-long disability.  There is as yet no treatment and no cure for this crippling disease, but Penn Medicine researchers are leading the effort to understand and develop therapies for FOP. 

About 800 people are affected by the disease worldwide, and most of them are known to the researchers at Penn Medicine, who have spearheaded FOP research. The work started when Frederick Kaplan, MD, met Michael Zasloff, who was then the Chief of the division of genetics at Children’s Hospital of Philadelphia (CHOP). Zasloff had started working on FOP at the National Institutes of Health prior to coming to CHOP, but progress was slow and patients were hard to find. Together, Kaplan and Zasloff launched a focused research effort, recruiting Eileen Shore, PhD to establish a new FOP Laboratory at Penn. Zasloff moved on to other endeavors but remains engaged with the FOP community.

After 15 years working together, Kaplan and Shore discovered the gene mutation that causes FOP. The discovery has led to a deeper understanding of what goes wrong in patients' tissues – and has led to potential avenues for therapy.

A series of investigations by Shore and Kaplan had implicated the BMP signaling pathway in FOP, however a major breakthrough for the FOP field happened when they identified the genetic culprit behind FOP:  a mutation in a bone morphogenetic protein (BMP) receptor gene called ACVR1/ALK2.  A single errant amino acid in the protein encoded by this gene is enough to disrupt the normal "on-off switch" function of the protein causing extensive FOP ectopic extra-skeletal (ectopic) bone. Strikingly, almost all classically affected individuals worldwide have the exact same amino acid change.

Having identified the cause of FOP, research investigations could be more directly focused on the molecular and cellular mechanisms that lead to the new bone formation in FOP, on the identities of the cells that participate in this process, and most importantly, on using this information to identify therapeutic strategies.

Shore and Kaplan and their research group quickly learned that the FOP mutation was a “gain-of-function” mutation that keeps the BMP signaling pathway on when it should be off. In one set of experiments that used the zebrafish as a model system, the FOP team and Penn colleague Mary Mullins confirmed that the mutant gene acts like a "leaky faucet." Unlike a water faucet that's either on or off, the mutant ACVR1/ALK2 gene is never completely off and is able to improperly switch on bone formation in response to signals generated through, for example, injury or inflammation.

In 2009, working in collaboration with researchers from the University of Connecticut, the FOP team found clues to the origin of the renegade bone-forming cells when they discovered that at least half of the cells in FOP that become ectopic bone are not derived from muscle cells as previously speculated, but are cells that appear to be immature stem cells at or near blood vessels that can be mobilized and induced to become cartilage and bone-forming cells.

Another surprising result was discovered, this time with Harvard researchers, that the FOP mutation can convert mature cells, which have already differentiated, back into stem cells, a finding with implications far beyond FOP.

In the past several years, it has now become possible to begin considering ways to control, treat, and perhaps even reverse the effects of FOP. 

In one interesting approach, reported in 2011, the FOP laboratory used a promising new strategy to directly block the mutated ACVR1/ALK2 gene.  Using a technique known as RNA inhibition, in which a specially engineered RNA molecule silences the expression of the mutant gene, the investigators were able to restore normal protein functioning in FOP-affected cells

The stem cell samples used in these experiments were among those obtained by the lab’s “Tooth Fairy" program. Since aberrant bone tissue formation can be triggered in FOP patients even by something as simple as a routine intramuscular injection, collecting tissue samples with biopsy or other surgical techniques is out of the question, and blood samples aren't very useful for detailed molecular analysis of the disease.  The "Tooth Fairy" program collects the baby teeth of children with FOP when the teeth are lost during the normal growth process.  The bone-forming cells from the tooth dental pulp proved an ideal source of samples for study with no risk to the patients.

While the RNA inhibition technique still needs to be confirmed with mouse models and further study before it could be developed into an effective treatment, it serves as an example of the great progress made by Penn researchers in the understanding of FOP, one of medicine's greatest mysteries.

Additional therapeutic strategies using novel molecules and inhibitors are presently under development in Shore and Kaplan’s Penn lab, and through collaborations with CHOP investigators and others.

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