Bone Abstracts (2015) 4 IS15 | DOI: 10.1530/boneabs.4.IS15

Achondroplasia-new therapy

Laurence Legeai-Mallet

INSERM U1163, Imagine Institute, Paris Descartes University, Paris, France.

Fibroblast growth factor receptor 3 (FGFR3) is an important regulator of bone formation. Achondroplasia (ACH) is the most common form of dwarfism; it involved FGFR3 gene mutations, in which skull, appendicular and axial skeletons are affected. The comparative analyses of the skeletal phenotype of Fgfr3 mice (Fgfr3Y367C/+) and patients with ACH showed, in both cases, short stature, defective proliferation, and differentiation of the chondrocytes in the growth plate cartilage, skull base anomalies with a complete absence of the synchondrosis and a reduction of the size of the occipital foramen. Both endochondral and membranous ossification processes are disrupted during development in ACH and Fgfr3Y367C/+mice. At cellular level, Fgfr3 gain-of-function mutations induce increased phosphorylation of the tyrosine kinase receptor FGFR3; which correlated with an enhanced activation of its downstream signaling pathways.

Potential therapeutic strategies have emerged for ACH. Several preclinical studies have been carried out: C-type natriuretic peptide (CNP) analog (BMN111), intermittent PTH injections, soluble FGFR3 therapy, meclozine and statin treatments. Among the putative targets to antagonize FGFR3 signaling, CNP (or BMN111) is one of the most promising strategies. BMN111 acts as a key regulator of longitudinal bone growth by down-regulating the MAPK pathway, which is activated as a result of FGFR3 gain-of-function mutation. Preclinical studies showed that BMN111 treatment led to a large improvement in skeletal parameters in Fgfr3Y367C/+mice. BMN111 is currently in clinical trial (phase 2) in pediatric patients with achondroplasia. Since the identification of the gene 20 years ago, the clinical trial marks the first big step toward real treatment for these patients.

Disclosure: The author declared no competing interests.

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