Gene Research Offers Hope for Sona
Work supports potential therapy for fatal bone disorder
Dressed in a blue fairy costume, 7-year-old Sona Brinkman dances around, offering no immediate hint that something’s wrong. Not even subtle cues, like the stiffness in her neck or the way she never lifts her arms above her head, suggest the serious nature of her condition.
Since age 5, Sona’s battled fibrodysplasia ossificans progressiva (FOP), a rare yet deadly genetic disorder that turns muscle, tendons and ligaments into bone. She recently had to give up gymnastics, because any injury—even the simple bumps and bruises of childhood—can spur abnormal bone growth.
FOP, commonly called “Stone Man Syndrome,” begins in childhood and over time builds a “second skeleton” that eventually locks a person in a prison of bone. More than a third of the 800 confirmed cases worldwide are patients in the United States[i].
Few doctors recognize the early signs of the disease, which include short, inwardly bent “big” toes and small lumps on the scalp, neck or back that appear in infancy and early childhood. In fact, it’s often misdiagnosed as cancer.
No one thought anything of the periodic small bumps on Sona’s scalp, but when a large lump persisted on her spine, she underwent a biopsy to rule out a tumor. Shortly afterward, her back and shoulders were covered in extra bone.
“We later learned it was an FOP flare-up, which is when the disease activates and the body begins the process of inappropriate bone formation,” says Sona’s father, Kyle Brinkman. “The surgery likely caused the flare-up, because biopsies are something you shouldn’t do with FOP, but we didn’t know that at the time.”
Such suffering can be avoided with a simple genetic test (see “Diagnosing FOP”). It’s a fact that Kyle Brinkman and Sona’s mom, Aarti Brinkman, MD, a family practitioner, hope to share with other parents and the medical community.
FOP is caused by a mutation in the gene ACVR1, which encodes a receptor that binds to a protein (Activin-A) that normally tells bone- and cartilage-producing cells to slow or stop growth. When mutated, ACVR1 reverses Activin-A’s role, causing it instead to trigger bone formation.
Most FOP cases result from a new mutation, such as a DNA copying error during fetal development, and occur in children with no family history of the disease.[ii]
You can’t remove the extra bone, because any trauma—including surgery—causes an FOP flare-up, a painful swelling that marks new bone development. Most cases, including Sona’s, are managed using pain medication, anti-inflammatory drugs and injury prevention.
Currently there is no cure. However, potential therapeutics are on the horizon, and OIC-funded research is helping to contribute to their development.
In a recent study published in Science Translational Medicine, researchers at the biotechnology company Regeneron stopped FOP-like bone growth in mice genetically modified to carry the mutant ACVR1 gene, using a custom-made antibody that targets and blocks Activin-A[iii].
But knocking out or diminishing gene activity can be dangerous unless you’re certain the body can fare well without it. Foundational work by OIC researcher Karen Lyons, PhD (pictured), has addressed this issue. Her team genetically modified mice to “knock out” the ACVR1 gene in cartilage cells and studied how its absence affected cartilage development. Although some defects in cartilage growth were noted, the mice remained healthy.
“That told us this gene’s function was not absolutely critical once cartilage has already formed, and that therapies that inhibit the activity of the mutant ACVR1 might be well-tolerated in humans,” says Lyons. “Our findings tell us that approaches such as the one used by the scientists at Regeneron are preferable for treating FOP.”
Lyons also serves as a scientific advisory board member for a competitive research grant program established by the Brinkman family and the International Fibrodysplasia Ossificans Progressiva Association to accelerate the development of potential FOP therapies. The program funds research focused on discovering therapies that may benefit patients in the near rather than distant future.
“This is a great example of how collaboration between a patient family, scientists and an organization like OIC can help forward the discovery of promising therapeutics for a disabling pediatric orthopaedic disease,” Lyons says.
For the Brinkmans, it’s an opportunity to raise awareness, help other patients, and move closer to a cure. “We feel there is a lot of hope and maybe even a cure possible in Sona’s lifetime,” says Kyle Brinkman.
Biopsies can cause flare-ups and accelerated bone growth in those with FOP.
A genetic test for FOP is suggested for children with the following symptoms:
- Big toes that are shortened and bent inward
- Neck stiffness
- Scalp lumps (even those that repeatedly go away)
- Painful swellings/nodules on the neck, back or chest that are often mistaken for cancer
[ii] NIH Genetics Home Reference | Fibrodysplasia ossificans progressiva http://ghr.nlm.nih.gov/condition/fibrodysplasia-ossificans-progressiva
[iii] Pullen LC. “Fibrodysplasia Ossificans Progressiva: Potential Therapy” Medscape Medical News. Sept. 2, 2015. Accessed Jan. 22, 2015 from http://www.medscape.com/viewarticle/850464, AND, Science Translational Medicine 02 Sep 2015: Vol. 7, Issue 303, pp. 303ra137 DOI: 10.1126/scitranslmed.aac4358