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Bone Abstracts (2019) 7 OC23 | DOI: 10.1530/boneabs.7.OC23

ICCBH2019 Oral Communications (1) (27 abstracts)

Effects of the FGF2 aptamer on growth plate cartilage development of achondroplasia patient-specific iPS cells in a xenograft model

Takeshi Kimura 1 , Kie Yasuda 1 , Yukako Nakano 1 , Shinji Takeyari 1 , Yasuji Kitabatake 1 , Takuo Kubota 1 , Yoko Miyoshi 1 , Keiichi Ozono 1 , Yosuke Nonaka 2 , Masatoshi Fujiwara 2 & Yoshikazu Nakamura 2

1Osaka University Graduate School of Medicine, Osaka, Japan; 2Ribomic Inc, Tokyo, Japan.

Objectives: Endochondral ossification in the growth plate cartilage (GPC) plays a crucial role in the determination of the length and shape of long bones. Many skeletal dysplasias are caused by GPC dysfunction, associated with short stature. We have already reported that human iPS cell-derived cartilage (hiPSC-Cart), when implanted into the subcutaneous spaces of the SCID mice for 4 weeks, formed skeletal tissue like GPC. This model could also recapitulate the pathology of FGFR3-related skeletal dysplasia (Osteoarthritis and Cartilage 2018). In the study, we applied our hiPSC-GPC model to the evaluation of candidate drug efficacy for FGFR3-relaed skeletal dysplasia.

Methods: We used 3 hiPSC lines derived from patients with achondroplasia (ACH) and one healthy control. A RNA aptamer, RBM-007, specific for human FGF2 and confirmed the blocking effect in signaling pathway induced by FGF2 in vitro was used as a candidate drug for ACH. First, ACH-hiPSCs were chondrogenically differentiated with various concentration of RBM-007. Then, ACH-hiPSC-derived cartilages were transplanted into SCID mice (a xenograft model). Four mice were treated with RBM-007, and the other 4 mice were treated with vehicle. Grafts were removed 6 weeks after transplantation and subjected to histological analysis.

Results: In in vitro experiments, control hiPSCs differentiated into chondrocytes and produced cartilage matrix, while ACH-hiPSCs did not differentiate into chondrocytes. 100 nM, but not 10 nM, RBM-007 promoted the chondrogenic differentiation of ACH-hiPSCs with characteristic safranin-O-positive matrix formation and improved the expression of the chondrocyte marker genes such as COL2A1. As a result of the xenograft model, histological analysis showed that control hiPSC-GPC had a zonal arrangement similar to GPC and is associated with bone formation. Each zone expressed marker gene such as type X collagen. Hypertrophic cells in ACH-hiPSC were smaller than those in control hiPSC-GPC. Treatment with RBM-007 improved the pathology of ACH, but did not normalize the hypertrophic cell size.

Conclusions: The experiments of the xenograft model suggest that RBM-007 is a potential drug for achondroplasia.

Disclosure: Keiichi Ozono is an adviser of Ribomic Inc. and had honorarium from Ribomic Inc. Yosuke Nonaka, Masatoshi Fujiwara, Yoshikazu Nakamura are employees of Ribomic Inc.

Volume 7

9th International Conference on Children's Bone Health


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