Skeletal development is a temporally-regulated non-linear process orchestrated by a complex genetic network that proceeds via two distinct ossification mechanisms, namely membranous and endochondral ossification. Genetic disorders of the skeletal system affect both bone and cartilage formation from early fetal development up to post-natal growth. Fibroblast growth factor receptor 3 (FGFR3) is an important regulator of bone formation. Achondroplasia is the most common form of dwarfism; it involved FGFR3 gene mutations, in which skull, appendicular and axial skeletons are affected. The understanding of disease mechanisms lead to targeted treatment. To date, the development of innovative therapies to treat achondroplasia is expanding. Several potential therapeutic strategies have emerged. Preclinical studies have been carried out: e.g. C-type natriuretic peptide analog (BMN111), intermittent PTH injections, soluble FGFR3 therapy, Meclozine, Statin and pan-FGFR tyrosine kinase inhibitor (NVP-BGJ398) 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. Today, BMN111 (vosoritide) is currently in clinical trial (phase 2) in pediatric patients with ACH. The first data show the improvement of the growth velocity in children with ACH and support the further development of vosoritide for the treatment of children with achondroplasia with open growth plates.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology