Achondroplasia (Ach) is a skeletal disorder caused by gain-of-function mutations of FGFR3. Ach patients suffer from various complications such as short stature, foramen magnum stenosis and sleep apnea. Disease-specific treatment is not available at present, although some drugs including a C-type natriuretic peptide analogue have been developed. The mutated FGFR3, G380R, has an elevated activity of the receptor-associated tyrosine kinase, but G380R is further activated by the binding of its ligand. Aptamer is a RNA-related drug with specificity to its cognate target or an active compound. We generated a RNA aptamer, RBM-007, specific for human FGF2 and confirmed the blocking effect in signaling pathway induced by FGF2 in vitro. In the study, we investigated the effects of RBM-007 in the transgenic Ach model mouse where G380R is expressed in chondrocytes under the type II collagen promoter. The Ach mice, Fgfr3Ach, had shorter body length than that of wild-type (wt) littermate mice, and the administration of 10 mg/kg RBM-007 sc. once every 2 days for 3 weeks significantly improved the body length (P=0.002) and femur length (P=0.0001). However, the treatment with RBM-007 did not normalized the length of the body and the femur in Fgfr3Ach. In addition, we performed in vitro chondrocytes differentiation experiments using ACH patients-derived iPS cells (iPSCs).The experiment was performed according to the protocol reported previously (Yamashita A et al. Nature 2014). In the experiments, control iPSCs differentiated into chondrocytes and produced cartilage matrix, while iPSCs derived from 3 Ach patients did not differentiate into chondrocytes. The results were consistent with those reported previously. 100 nM, but not 10 nM, RBM-007 promoted the chondrogenic differentiation of Ach-iPSCs with characteristic safranin-O-positive matrix formation and improved the expression of the chondrocyte marker genes such as SOX9, COL2A1and ACAN. We are now checking side effects of RBM-007 on the growth plate using young model monkeys. These results suggest that RBM-007 is a potential drug for achondroplasia.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology