Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease in which heterotopic bone forms in muscle and soft tissue, leading to joint dysfunction and significant disability. FOP is progressive and many patients are wheelchair‐bound by the 3rd decade of life. FOP is caused by an activating mutation in the ACVR1 gene, which encodes the activin A Type 1 receptor. Aberrant signalling through this receptor leads to abnormal activation of the pSMAD 1/5/8 pathway and triggers the formation of bone outside of the skeleton. There is no curative therapy for FOP; however, exciting advances in novel therapies have developed recently. Here, we review the clinical and translational pharmacology of three drugs that are currently in clinical trials (palovarotene, REGN 2477 and rapamycin) as well as other emerging treatment strategies for FOP.

Inhibition of phosphatidylinositol 3‐kinase α (PI3Kα) prevents heterotopic ossification

“…Over the last years, beyond anti‐inflammatory drugs, potential treatments for FOP have been developed and are currently in ongoing clinical trials. Some treatments focus on ACVR1 activation (e.g., anti‐activin A antibody or ACVR1 kinase inhibitors), while others, such as the PI3Kα inhibitors presented here, target cells and signaling pathways required for heterotopic ossification downstream ACVR1 (e.g., palovarotene or rapamycin; Wentworth et al , ). ACVR1 is almost ubiquitously expressed, and the pathways targeted by these drugs are also involved in multiple physiological and developmental processes.…”

Selective Agonists of Nuclear Retinoic Acid Receptor Gamma Inhibit Growth of HCS‐2/8 Chondrosarcoma Cells

“…One of the reasons for this is due to adverse side effects including dry skin, dry mucous membranes, headache, nausea and vomiting, rash, mouth sores, and vision changes . Targeting retinoic signaling using selective agonists for one specific RAR receptor is likely more effective because RARγ agonists have shown good side effect profiles in preclinical and clinical studies . The molecular mechanisms of RARγ agonists on inhibition of growth of HCS‐2/8 cell tumors may include inhibition of synthesis of cartilaginous matrix proteins and suppression of cell proliferation.…”

“…Notably, palovarotene is currently being investigated in phase 3 clinical trials for the treatment of fibrodysplasia ossificans progressiva (FOP) (http://Clinicaltrials.gov registration NCT02190747, phase 3) and multiple osteochondromas (NCT03442985, phase 2). Considering previous findings of both RA and palovarotene on cartilage biology in the setting of multiple pathologic conditions and the fact that it is well‐tolerated in clinical trials, we hypothesized that RARγ agonists including palovarotene would have an in vitro and in vivo effect on the human chondrosarcoma cell line, HCS‐2/8, which has been established from a low‐grade human chondrosarcoma cell line . The findings obtained in this study suggest that selective RARγ agonists including palovarotene may provide an anti‐tumor effect on low‐grade human chondrosarcoma cells.…”

Characteristics of the odontological management of patients with progressive ossifying fibrodyplasia

“…Progressive ossifying fibrodysplasia (POF) is a rare autosomal dominant disorder characterized by congenital malformation of the big toes and progressive postnatal heterotopic ossification of the soft tissues with characteristic anatomic profiles [1][2][3][4][5]. The first heterotopic ossifications usually occur before the age of 10 years and mainly affect the tissues surrounding the hips, spine, and joints [6,7]. The outbreaks are episodic; immobility is cumulative.…”