Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic musculoskeletal disease (OMIM: #135100) with a reported prevalence of approximately 1 in 2 million. Patients with FOP develop extra-skeletal plaques of endochondral bone (termed heterotopic ossification, HO) in connective tissues within muscles, tendons, ligaments, and fascia, through painful inflammatory episodes termed “flare-ups”. Flare-ups often start during the first decade of life, and resulting ossifications progressively compromise motility and balance in affected individuals, who eventually rely on a wheelchair by their thirties. In addition to the progressive immobility, FOP patients are at high risk of life-threatening complications, like severe pneumonia and right-sided heart failure. Since muscle damage triggers HO, invasive surgery to retrieve ectopic bone plaques is not recommended. Unfortunately, still nowadays, there is no validated cure for FOP, and biomarkers to monitor disease progression remain to be established.
Since the first reported cases of FOP, also known as the stone man syndrome, this devastating disease has become a prime example how knowledge about the disease pathology can open new avenues for diagnostic and treatment possibilities. For years, FOP was diagnosed after a highly penetrant and characteristic malformation of the great toe. In 2006, the discovery of a single point mutation in the gene ACVR1 made it possible to diagnose this devastating condition by molecular testing early in childhood (ideally after birth), before ectopic ossification is apparent. The ACVR1 gene encodes for the protein ALK2, a membrane receptor with intrinsic kinase activity mediating signal transduction in response to soluble Bone morphogenetic protein (BMPs) ligands. The first studies reported from molecular biology labs investigating the most common ACVR1 mutation in FOP (encoding the ALK2 R206H mutant receptor) reported how this mutation altered BMP signalling responses, overactivating the pathway and inducing the expression of genes involved in chondrogenic and osteogenic differentiation. Importantly, these results led to subsequent experiments demonstrating that enzymatic inhibition of ALK2 successfully prevents osteogenic differentiation in vitro, as well as in FOP-like animal models of the disease. More than a decade later, some of the most advanced drugs currently in clinical trials for FOP precisely target ALK2 activity either directly (i.e., Saracatinib, AstraZeneca; IPN60130, IPSEN Pharma) or its downstream induced signalling (i.e., Palovarotene, IPSEN Pharma). Two major breakthroughs in FOP research were achieved relatively recently, substantially facilitating drug development. First, the generation of induced pluripotent stem cells (iPSCs) from somatic tissue biopsies (i.e., blood cells, skin fibroblasts, urine cells), allows for an (in theory) unlimited source of patient-derived cells to investigate disease mechanisms and perform drug screenings. In combination with the Nobel prize awarded technique CRISPR/Cas9 gene editing to correct the mutant ACVR1 gene in FOP iPSCs, today it is possible to unveil cell responses and druggable mechanisms directly linked with ALK2 R206H. Second, the generation of a conditional transgenic mouse model of FOP expressing the mutant ALK2 R206H receptor in a stable and reliable manner, offers a testing platform where the effects of potential therapies in ectopic bone development can be quantified. Noteworthy, these two novel tools allow to study the effects driven by endogenous ALK2 R206H expression, unlike non-physiological overexpression approaches used in the past. In the recent years, FOP mice and iPSCs studies have revealed a prominent role for a circulating type of growth factor named Activins. Activins are known to be released under inflammatory episodes, and were shown to specifically activate the mutant ALK2 R206H, thereby inducing HO. After successful preclinical studies in FOP mice with an anti-Activin specific monoclonal antibody, clinical trials were initiated in patients (Garetosmab, Regeneron Inc.), which already have reported promising results.
While we still wait for the output of the ongoing clinical studies, new potential therapeutic molecules are continuously been identified through preclinical studies, which are waiting to be tested in patients with FOP. However, the lack of patients available to enrol in new studies is becoming a major bottleneck for drug development in FOP. An approach to overcome this issue might be to further refine the drugs, for example by performing exhaustive preclinical disease-specific toxicity tests, thereby minimizing the chance that drugs in advanced stages of clinical trials fail due to undesirable side effects. In summary, bench-to-bedside research has led us to exciting times for drug development in FOP. We hope that clinicians will soon have available a repertoire of targeted and safe drugs to improve the quality of life of patients with FOP.
More information can be found at https://www.ifopa.org/ongoing_clinical_trials_in_fop