A study in Science Translational Medicine
reveals new information on the pathophysiology of Fibrodysplasia Ossificans Progressiva (FOP) — a rare, progressive, severely disabling, and eventually fatal disease in which muscles, ligaments, tendons and other connective tissues are transformed into bone. One of the study’s researchers compared the molecular interactions that lead to the development of FOP to that of stepping on the brakes of a car and having it accelerate (see interview below)
There are an about 800 confirmed cases of FOP in the world, including approximately 200 in the United States. There is currently no effective treatment for this very rare condition.
The study was undertaken by the researchers at Regeneron Pharmaceuticals and it offers a path to developing a treatment for this fatal condition.
FOP is caused by mutations in ACVR1
, a gene that encodes for the ACVR1 receptor protein.
Under normal conditions, ACVR1 receptor protein is involved with bone growth. More specifically, when Bone Morphogenetic Proteins (BMPs) bind to the ACVR1 receptor, a cascade of intracellular events results. This signaling helps form bones. The team at Regeneron determined that in addition to BMPs, another ligand, Activin A, can also engage ACVR1 but that when it does so it turns off the ACVR1-BMP signaling. What is surprising in the new study, the researchers observed that in a mouse model of FOP, the ligand Activin A, acting through the mutant ACVR1 receptor, turned on the ACVR1-BMP signaling rather than turning it off.
The switch in the function of Activin A in these complex receptor-ligand interactions is believed to be the cause of FOP pathophysiology and equally important, this knowledge can be used to develop a treatment for these patients.
In an exclusive interview with Rare Disease Report, Aris Economides Executive Director of Skeletal Diseases Therapeutic Focus Area and Genome Engineering Technologies at Regeneron, and co-founder of the Regeneron Genetics Center talked about the study and its overall implications in understanding FOP and developing a possible treatment.
How Is ACVR1 Involved with the Pathophysiology of FOP?
The question that we initially set out to answer was “whether the process by which ACVR1 R206H, this mutant receptor, makes or drives this abnormal bone formation in FOP, requires the binding of a ligand or whether it does not.” This is a very simple question and practical one because, for us, depending on the answer to this question, we will be thinking about this disease from a drug development standpoint quite differently.
What we found was unexpected is that this mutant receptor binds a ligand called activin and uses it as a signal-inducing factor. …. . So, in people who are not FOP patients and hence have the wild-type version of ACVR1, Activin A is a natural antagonist of BMP signaling mediated through ACVR1. Whereas, in FOP patients, the very same ligand, the mutant ACVR1 receptor is perceived as a signal reducing factor.
Imagine that you are driving and you’re going to come to a red light, and you’re going to press on the brakes of your car and your will stop which is exactly what’s supposed to happen. Well, if you or your car is an FOP patient, instead of stopping, when you press on the brakes the car accelerates even further and all hell breaks loose.
Can a treatment be developed based on that discovery?
We were lucky because we had generated these anti-Activin A antibodies for another program…..we tested them in our mouse model of FOP and we showed that if you treat mice that are on their way to develop this heterotopic ossification because they express this mutant receptor, just like the one in humans, the antibody completely blocks that process. And no other ligand rises to the occasion and replaces Activin A. This led us to conclude in our paper that Activin A is necessary and sufficient to drive heterotopic ossification in our mouse model of FOP.
What outcome was measured in the mouse model?
We took X-rays using a machine called an in vivo
microCT. It’s basically a whole body X-ray that allows you to image the mouse in 3D and you can look at the whole skeleton in detail. You can download images from the AAAS website
showing there is massive ossification of the skeletal muscles and the ligaments…..And the mouse cannot flex its joint. It’s completely, completely locked in that configuration, just as you see in FOP patients.
Can this study revolutionize how some preclinical studies are performed?
I think it’s a quite nice story. For me it (the paper in Science Translational Medicine) represents a blueprint of the kinds of strategies that we want to use for not only understanding FOP, we think we’ve done an okay job here, but really to serve as a blueprint for looking at other rare and neglected diseases and try to understand them at the level of their molecular pathophysiology, to the level where we can provide an adequate understanding that hopefully will lead to drug development, perhaps re-purposing even of existing drugs.
Hatsell SJ, Idone V, Wolken DMA, et al. CVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med. Published online ahead of print, Sept 2, 2015. DOI: 10.1126/scitranslmed.aac4358