Longitudinal Imaging of the Skull Base Synchondroses Demonstrate Prevention of a Premature Ossification After Recifercept Treatment in Mouse Model of Achondroplasia.

Achondroplasia is the most common form of short-limb dwarfism. In this disorder, endochondral ossification is impaired due to gain-of-function mutation in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene. In addition to short limbs, cranial base bones are also affected leading to shortening of the skull base and to serious neurological complications associated with foramen magnum stenosis. These complications are thought to be due to the delay or premature arrest of skull base growth, caused by an accelerated ossification of the sphenooccipital (SOS) and the intraoccipital (IOS) synchondroses. Skull synchondroses consist of two opposite growth plates sharing a common reserve zone of chondrocytes. In this study, we first characterized the skull base synchondroses ossification in a mouse model of achondroplasia carrying the human G380R mutation (Fgfr3 ach/+ ). We then addressed whether Recifercept, a soluble FGFR3, could prevent premature closure of these synchondroses. Postnatal radiological observations revealed the presence of bony bridge structures in one or more synchondroses in Fgfr3 ach/+ mice as early as postnatal day 3 in the most severe cases. The presence of early ossification correlated with the severity of the disease as it was associated with an arrest of the cranial base bone growth. Histological analyses indicated changes in the synchondroses structure and matrix proteoglycan contents confirming a process of ossification. Treatment of Fgfr3 ach/+ mice with Recifercept compared with vehicle prevented premature synchondrosis ossification and the transition to bone, resulting in improved skull shape and cranium ratio. Given the impact of Recifercept on synchondrosis inactivation, it is possible that it could prevent one of the most severe complication of achondroplasia if used early enough during bone development. These data support the clinical development of Recifercept for achondroplasia, and suggests that early treatment may be required to best address impaired endochondral bone growth. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

In vitro and in vivo characterization of Recifercept, a soluble fibroblast growth factor receptor 3, as treatment for achondroplasia.

Achondroplasia is a rare genetic disorder caused by mutations in the Fibroblast Growth Factor receptor 3 (FGFR3). These mutations lead to aberrant increase of inhibitory signaling in proliferating chondrocytes at the growth plate. Recifercept is a potential treatment for this disease using a decoy approach to sequester FGFR3 ligands subsequently normalizing activation of the mutated FGFR3 receptor. Recifercept binds to FGF isoforms in vitro and in cellular model systems and reduces FGFR3 signaling. In addition, in a transgenic mouse model of achondroplasia, Recifercept restores reduced body weight and long bone growth in these mice. These data suggest that Recifercept treatment could lead to clinical benefits in children treated with this molecule.