Abstract
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.
Highlights
Mutations in the gene encoding fibroblast growth factor receptor 3 (FGFR3) are responsible for the phenotypes of several skeletal chondrodysplasias, including achondroplasia, the most common form of short limb and short stature
Binding between Recifercept and human FGFs isoforms was determined by surface plasmon resonance spectroscopy (SPR)
Recifercept was immobilized on a CM5 chip and each FGF subfamily was analyzed on a new immobilized chip. hFGF9 was used as an internal run control and was loaded before and after the tested subfamilies
Summary
Mutations in the gene encoding fibroblast growth factor receptor 3 (FGFR3) are responsible for the phenotypes of several skeletal chondrodysplasias, including achondroplasia, the most common form of short limb and short stature. Children affected by achondroplasia suffer from abnormal long bone development, resulting in growth deficits [1]. They develop deformations of the skull and vertebrae leading to severe neurological and orthopedic complications. Most of the patients with the typical clinical features of achondroplasia have a spontaneous point mutation that results in a glycine to arginine substitution at amino acid 380 (G380R) located in the transmembrane domain of FGFR3 [3, 4].
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