Cause of Rare Genetic Bone Disease Described
News Sep 08, 2015
FOP is a progressive, severely disabling and ultimately fatal disease in which muscles, ligaments, tendons and other connective tissues are transformed into bone. FOP is caused by mutations in ACVR1, a gene that encodes for the ACVR1 receptor protein. When a set of ligands (proteins that help regulate cell behavior) known as Bone Morphogenetic Proteins (BMPs) bind to the ACVR1 receptor, a cascade of intracellular events (referred to as "signaling") is induced. This signaling is critical in controlling the formation of the skeleton and ensuring normal bone growth.
Regeneron scientists found that another ligand, Activin-A, in combination with the ACVR1 protein, normally "turns off" signaling by the BMPs, and is thus believed to play a role in regulating the volume of bone growth. However, they also discovered that in the presence of the ACVR1 mutation, Activin-A instead "turns on" BMP signaling, driving the abnormal bone growth that is characteristic of FOP.
People diagnosed with FOP are gradually debilitated and immobilized as the soft tissue throughout their body transforms into bone. Attempts to remove this extra bone through surgery only result in additional episodes of abnormal bone growth. There are approximately 800 confirmed cases of FOP in the world, including around 200 in the United States, and the current lack of effective treatments underscores the need for scientific exploration that may aid in the development of new therapies.
"We are excited and grateful to have this new fundamental insight into FOP," said Betsy Bogard, Global Research Development Director of the International FOP Association (IFOPA). "Regeneron's extraordinary research findings bring new hope to the families who struggle with this devastating disease on a daily basis."
To extend their findings in vivo, Regeneron scientists used the Company's proprietary VelociGene® technology to develop a genetically humanized and novel mouse model of FOP in which the hypothesized molecular pathophysiology of disease was confirmed. The team also used Regeneron's VelocImmune®, a platform that enables the rapid generation of fully human monoclonal antibodies, to generate and validate a potential therapeutic antibody chosen for its ability to potently and selectively block Activin-A. Regeneron continues active preclinical testing on this antibody.
"We have been touched and motivated by the stories of people with FOP, and are grateful to contribute to the understanding of this disease in a way that may lead to new therapeutic options," said Aris N. Economides, Executive Director of Skeletal Diseases Therapeutic Focus Area and Genome Engineering Technologies at Regeneron, and co-founder of the Regeneron Genetics Center. "Gaining insight into the Activin A-related mechanism is a tremendous step forward for researchers, and the knowledge gained about receptor-ligand interactions and signaling in this system may prove relevant in other diseases, as well."