The Horizon of a Therapy for Rare Genetic Diseases: A “Druggable” Future for Fibrodysplasia Ossificans Progressiva

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition characterized by progressive extra-skeletal ossification leading to cumulative and severe disability. FOP has an extremely variable and episodic course and can be induced by trauma, infections, iatrogenic harms, immunization or can occur in an unpredictable way, without any recognizable trigger. The causative gene is ACVR1, encoding the Alk-2 type I receptor for bone morphogenetic proteins (BMPs). The signaling is initiated by BMP binding to a receptor complex consisting of type I and II molecules and can proceed into the cell through two main pathways, a canonical, SMAD-dependent signaling and a p38-mediated cascade. Most FOP patients carry the recurrent R206H substitution in the receptor Glycine-Serine rich (GS) domain, whereas a few other mutations are responsible for a limited number of cases. Mutations cause a dysregulation of the downstream BMP-dependent pathway and make mutated ACVR1 responsive to a non-canonical ligand, Activin A. There is no etiologic treatment for FOP. However, many efforts are currently ongoing to find specific therapies targeting the receptor activity and the downstream aberrant pathway at different levels or targeting cellular components and/or processes that are important in modifying the local environment leading to bone neo-formation.

Bis-Heteroaryl Pyrazoles: Identification of Orally Bioavailable Inhibitors of Activin Receptor-Like Kinase-2 (R206H)

“…N-(4-Methoxyphenyl)-4-(1-propan-2-yl-3-pyridin-3-ylpyrazol-4-yl) 4-(1-Ethyl-3-pyridin-3-ylpyrazol-4-yl)-N-(4-piperidin-4ylphenyl)pyrimidin-2-amine (18f) The title compound 18f was prepared from compound 17 and tert-butyl 4-(4-aminophenyl)-1-piperidinecarboxylate following a procedure similar to that used to prepare compound 18e. 1 Expression and Purification of ALK2 (R206H) The ALK2 kinase domain including residues 201 to 499 with the R206H mutation was expressed with a recombinant baculovi-rus expression system. Sf9 cells were inoculated at 27°C and harvested 48 h after infection.…”

“…Fibrodysplasia ossificans progressiva (FOP) is a rare disorder that shows progressive heterotopic ossification in the muscles, tendons, or ligaments with an incidence of 1 in 2 million individuals. 1,2) FOP is caused by abnormal activation of bone morphogenetic protein (BMP) signaling due to highly recurrent mutations, including R206H in activin receptor-like kinase-2 (ALK2) (encoded by ACVR1 gene), a subtype of BMP type-I receptors, resulting in an alteration in the intracellular glycine-serine-rich domain of the enzyme. Diffuse intrinsic pontine glioma (DIPG), a fatal brain cancer that forms in the brainstem of children, is another disease caused by the R206H mutation of ALK2.…”

“…-NMR (270 MHz, CDCl 3 ) δ: 8.85-8.86 (1H, m), 8.62 (1H, d, J = 1.6, 4.6 Hz), 8.23-8.28 (2H, m), 8.04 (1H, s), 7.88-7.92 (1H, m), 7.71 (1H, s), 7.30-7.35 (1H, m), 6.87-6.94 (3H, m), 6.56 (1H, d, J = 5.4 Hz), 4.25-4.33 (2H, m), 1.61 (3H, t, J = 7.3 Hz). LC/MS (ESI): m/z 373 [M + H] + .N-[4-(Difluoromethoxy)phenyl]-4-(1-ethyl-3-pyridin-3-ylpyrazol-4-yl)pyrimidin-2-amine (18d)The title compound 18d was prepared from compound 17 and 4-(difluoromethoxy)aniline following a procedure similar to that used to prepare compound 18b 1. H-NMR (270 MHz, CDCl 3 ) δ: 8.83 (1H, d, J = 1.1 Hz), 8.61-8.62 (1H, m), 8.26 (1H, d, J = 2.7 Hz), 7.99 (1H, s), 7.90 (1H, d, J = 4.3 Hz), 7.46 (2H, d, J = 4.6 Hz), 7.29-7.34 (1H, m), 7.01-7.23 (3H, m), 6.31-6.62 (2H, m), 4.27-4.31 (2H, m), 1.57-1.63 (overlapped by a water signal, 15H, t).…”

Atypical Presentation of Fibrodysplasia Ossificans Progressiva: A Case Report and Review of Literature

“…After the breakthrough discovery of the genetic basis of FOP, research trials have begun targeting various potential aspects and areas of the BMP signalling pathway, and various cell models are being prepared. The current research strategies are targeting dysregulated BMP signalling with agents like Dorsomorphin, Perhexiline and Imatinib mesylate; neofunction of the mutated ACVR1 receptor with anti-ActA antibodies and Rapamycin; the chondrogenetic differentiation processes with retinoic acid receptor gamma agonists like Palovarotene; the expression of the mutated receptor; the immune system with corticosteroids; as well as the local microenvironment of the lesions [ 17 - 19 ]. Although there has been significant progress in basic and translational research in FOP in the recent past, a lot of knowledge is yet to be unearthed.…”

Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva

“…The relationship between retinoid signalling and chondrogenesis is antagonistic: several elegant studies have shown that skeletal precursor cells treated with at RA, and with subsequent activation of retinoid signalling, have repressed chondrogenesis and cartilage formation . By allowing chondrogenesis to proceed only in the absence of retinoid signalling, this mechanism helps keep mesenchymal condensations in their prechondrogenic state and blocks differentiation into chondroblasts .…”