Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice.
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.
INSERM, U1065, Team 8, Mediterranean Center for Molecular Medicine, 06204 Nice, France.
Stéphanie
S
Garcia
Béatrice
B
Dirat
Thomas
T
Tognacci
Nathalie
N
Rochet
Xavier
X
Mouska
Stéphanie
S
Bonnafous
Stéphanie
S
Patouraux
Albert
A
Tran
Philippe
P
Gual
Yannick
Y
Le Marchand-Brustel
Isabelle
I
Gennero
Elvire
E
Gouze
D000130:Achondroplasia / Q000188:drug therapy*; D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
D051498:Receptor, Fibroblast Growth Factor, Type 3