04 September 2015

Antibodies against the "stone man syndrome"

The "culprit" of hereditary ossification of soft tissues has been found


A group of geneticists and biochemists from the biotechnology companies Regeneron Genetics Center Inc. and Regeneron Pharmaceuticals Inc. revealed the mechanism of transformation of muscle and connective tissue into bone growths in congenital genetic disease – ossifying progressive fibrodysplasia (FOP). Scientists have found that the key role in the pathological transformation of cells is played by the protein activin A. The results of the work are published in the journal Science Translational Medicine: Hatsell et al., ACVR1 R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A (briefly reported by the press release Regeneron Discovery on Cause of Rare Genetic Bone Disease Detailed in Science Translational Medicine Publication – VM).

The skeleton of a patient with ossifying progressive fibrodysplasia. 
Photograph: Wikimedia Commons

FOP is a very rare and severe genetic disease in which soft tissues progressively turn into bones. This leads to severe disability and often to death at an early age. The trigger, including tissue degeneration, is often bruises, inflammation, minor injuries. However, it happens that the disease worsens for no apparent reason. Back in 2006, it was found that 97 percent of sufferers of this disease have a mutation of the ACVR1 gene encoding special proteins on the cell surface – activin A receptors. 

Scientists bred mice with a similar genetic mutation and symptoms of FOP (which was quite difficult, since most of these mice die in the womb). At the first stage of the study, biochemists gave mice a special drug that blocked ACVR1 receptors and prevented any of their ligands from contacting them. This led to the disappearance of the symptoms of FOP. From which it followed that the pathological activity of cells is not related to the receptors themselves, but to the effect of a certain ligand. 

At the second stage of the experiments, scientists implanted special tampons with potential ligands for the receptor in mice. To the surprise of the researchers, tampons soaked with activin A were ossified (turned into bone tissue). The fact is that although ACVR1 is an activin A receptor, the latter has never been suspected of pathological effects: in healthy people, on the contrary, it blocks the receptor, preventing it from binding to other ligands (for example, morphogenesis proteins responsible for the growth and regeneration of bone tissue). 

Having understood the mechanism of the disease, scientists were able to quickly develop an experimental therapy based on monoclonal antibodies against activin A. After the introduction of antibodies, mice remained healthy for up to 6 weeks and did not show any symptoms.

Activins are special proteins, growth factors that play an important role in embryonic development (especially in the differentiation of mesoderm cells from which muscle and bone tissue develop). Also, together with inhibins, they are involved in the regulation of the activity of the sex glands (ovaries and testicles), secretion and menstrual cycle. But most importantly, activins are involved in the immune response of the body and are produced in all types of inflammation, which once again confirms their connection with FOP.

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