Postnatal Soluble FGFR3 Therapy Rescues Achondroplasia Symptoms and Restores Bone Growth in Mice

Abstract

Achondroplasia is a rare genetic disease characterized by abnormal bone development, resulting in short stature. It is caused by a single point mutation in the gene coding for fibroblast growth factor receptor 3 (FGFR3), which leads to prolonged activation upon ligand binding. To prevent excessive intracellular signaling and rescue the symptoms of achondroplasia, we have developed a recombinant protein therapeutic approach using a soluble form of human FGFR3 (sFGFR3), which acts as a decoy receptor and prevents FGF from binding to mutant FGFR3. sFGFR3 was injected subcutaneously to newborn Fgfr3(ach/+) mice-the mouse model of achondroplasia-twice per week throughout the growth period during 3 weeks. Effective maturation of growth plate chondrocytes was restored in bones of treated mice, with a dose-dependent enhancement of skeletal growth in Fgfr3(ach/+) mice. This resulted in normal stature and a significant decrease in mortality and associated complications, without any evidence of toxicity. These results describe a new approach for restoring bone growth and suggest that sFGFR3 could be a potential therapy for children with achondroplasia and related disorders.

FGFR3/fibroblast growth factor receptor 3 inhibits autophagy through decreasing the ATG12–ATG5 conjugate, leading to the delay of cartilage development in achondroplasia

“…STAT, MAPK1/3, PI3K-AKT, IHH, PTHLH/PTHrP and BMP are involved in the pathogenesis of chondrodysplasia caused by FGFR3 mutations. 15,53 NPPC (natriuretic peptide C), 54 NPPC analog, 55 FGFR3-binding peptide, 41 PTH, 13 soluble FGFR3 56 and statin 57 were found to partially rescue the retarded bone growth of ACH. While the efficacy and safety of these treatments require further investigation, understanding of more detailed molecular mechanisms will help developing better therapies for achondroplasia.…”

Fibroblast growth factor signaling in skeletal development and disease

“…Meclozine functioned to enhance bone growth in explant culture and increase bone growth in wild-type and achondroplasia mice (Matsushita et al 2013(Matsushita et al , 2015. Inhibition of ligands that activate FGFR3 can be achieved through expression of a soluble extracellular domain of FGFR3 (sFGFR3) that can compete with endogenous FGFR3 by binding FGF ligands such as FGF9 and FGF18 that functionally regulate the growth plate (Liu et al 2002(Liu et al , 2007Ohbayashi et al 2002;Hung et al 2007;Garcia et al 2013). Subcutaneous injections of recombinant sFGFR3 in a mouse model for achondroplasia was found to decrease mortality and improve skeletal growth (Garcia et al 2013).…”

“…Inhibition of ligands that activate FGFR3 can be achieved through expression of a soluble extracellular domain of FGFR3 (sFGFR3) that can compete with endogenous FGFR3 by binding FGF ligands such as FGF9 and FGF18 that functionally regulate the growth plate (Liu et al 2002(Liu et al , 2007Ohbayashi et al 2002;Hung et al 2007;Garcia et al 2013). Subcutaneous injections of recombinant sFGFR3 in a mouse model for achondroplasia was found to decrease mortality and improve skeletal growth (Garcia et al 2013). Inhibitory antibodies that specifically target the FGFR3 extracellular domain have been developed as potential cancer therapeutics but have not been evaluated for treatment of achondroplasia (Martinez-Torrecuadrada et al 2005;Hadari and Schlessinger 2009;Qing et al 2009).…”

Neutral Endopeptidase-Resistant C-Type Natriuretic Peptide Variant Represents a New Therapeutic Approach for Treatment of Fibroblast Growth Factor Receptor 3–Related Dwarfism

“…Garcia et al, 2013 demonstrated that a soluble fibroblast growth factor receptor-3 (sFGFR3) could act as a decoy receptor to prevent fibroblast growth factor (FGF) from binding to and signaling through the FGFR3. In vitro binding studies with fixed concentrations of FGF2, FGF9, and FGF18 demonstrated that sFGFR3 was required in 100-fold excess to reduce the concentration of these FGFs by one-half.…”