Turning into a bone

“Turning into a bone”: Fibrodysplaisa Ossificans Progressiva (FOP) awareness day. By Vladislav Grachev, Head of Central Federal District Branch of Interregional Public Organization “Living with FOP”, Russia.
April, 23rd is an international FOP awareness day. Fop is also known as a “stone man syndrome” or as a “second skeleton disease”. Fibrodysplaisa Ossificans Progressiva is a rare autosomal dominant genetic condition affecting 1 in 2 million people. One year ago polit.ru had already described FOP. Today we are talking about success in FOP treatment.
In FOP inflammation processes occur in tendons, fascia, aponeurosis and muscles, leading to calcification and ossification. A FOP progress during lifetime though in each patient progress is highly individual. FOP affects different muscle groups and connective tissue structures, usually spreading downwards – from neck to legs. By age of 30 most patients are handicapped having a “second skeleton” grown upon them. By age of 40 or 50 most patients die due to comorbid conditions. One of the most frequent causes of death is lung infection secondary to hypoventilation. Hypoventilation is caused by affection of intercostal muscules and thus reduction of lung vital capacity, which also leads to oxygen deficiency and heart failure. Also lethal outcomes due to cachexia were described, occurred because of affection of jaw muscles and swallowing muscles.
FOP is caused by mutations in ACVR1 gene, located in 2q23-q24. More than half FOP cases are determined by “major” p.Arg206His mutation. Gene ACVR1 encodes activin A receptor, type I – a member of BMP-receptors. BMP, or Bone Morphogenetic Proteins, are regulatory proteins responsible for embryonic bone tissue formation and post-natal bone repair. Most of the FOP cases are caused by de novo mutations though family cases have also been described. In 2008-2009 biologists, geneticists and doctors of University of Pennsylvania and Thomas Jefferson University of Philadelphia (USA) having worked with mice with ACVR1 gene defect identical to human FOP received encouraging results. The used substance had not only stopped the progression of the disease in mice, but had even shown some converse effect, lowering the activity of inflammation processes in affected tissues. The substance in question was
vitamin A1 (retinoid) acid specific to RAR-; receptors.
For a long time the laboratory in University of Pennsylvania where the ACVR1 mutation had been discovered was the only one investigating FOP. Nowadays research is conducted in Holland, UK, North Korea, Japan, China and other countries. The results of investigations were approved to be perspective and soon the product license was sold to a pharmaceutical company. The pharmaceutical company instantly proceeded to clinical trials which showed some satisfactory results. In summer 2014 in USA and in January 2015 in France the 2nd phase of clinical trials was started. Now the trials are held in three clinics – two in USA and one in France.
Approximately 50 FOP patients participated in clinical trials so far. According to press-release of pharmaceutical company, during first 6 weeks of 2nd phase of clinical trials in which 8 FOP patients had participated, there were no safety concerns detected. The 2nd phase of clinical trials is now to be continued. A group of 16 patients will receive the underdose of medicine. The 2nd phase is a double-blind placebo-controlled trial. The purpose of 2nd phase is to evaluate the effect of different doses of medicine on bone formation in FOP patients before and after flare-ups. The 2nd phase is to be finished by the end of 2015.
There is also some good news for more than 50 FOP patients living in Russia. Interregional Public Organization “Living with FOP” had managed to get a prior consent for holding a 3rd phase of clinical trials of retinoid-based medicine in Russia. The prior consent was given by Ministry of Health of Russian Federation and by pharmaceutical company’s representatives. In summer 2015 in Ministry of Health negotiations are scheduled. If they succeed, clinical trials in Russia will start in 2016. You can all the information and additional materials on the official cite of “Living with FOP” community.
The proof of retinoid acid efficiency can signify a lot for further research. The retinoid-based medicine can possibly effect upon other types of ossification and bone diseases, including osteoporosis. It is regretful that despite of retinoid acid research and application in different fields of medicine and pharmacology in Russia there are no investigations in the branch of bone pathology. If due to the efforts of “Living with FOP” community 3rd phase of clinical trials will take place in Russia, it is possible that Russian researchers will be interested in feasibility of using the medicine for bone pathology treatment.
On July 31st, 2015, the second FOP conference will take place in Moscow. The results of clinical trials will also be presented at the conference. FOP patients from Russia and former USSR countries will meet for communication and for participation in world’s best FOP specialists’ clinical examination. Organizers will gratefully accept any help – volunteer or\and financial.