Achondroplasia is the most prevalent genetic form of dwarfism in humans and is caused by activating mutations in FGFR3 tyrosine kinase. The clinical need for a safe and effective inhibitor of FGFR3 is unmet, leaving achondroplasia currently incurable. Here, we evaluated RBM-007, an RNA aptamer previously developed to neutralize the FGFR3 ligand FGF2, for its activity against FGFR3. In cultured rat chondrocytes or mouse embryonal tibia organ culture, RBM-007 rescued the proliferation arrest, degradation of cartilaginous extracellular matrix, premature senescence, and impaired hypertrophic differentiation induced by FGFR3 signaling. In cartilage xenografts derived from induced pluripotent stem cells from individuals with achondroplasia, RBM-007 rescued impaired chondrocyte differentiation and maturation. When delivered by subcutaneous injection, RBM-007 restored defective skeletal growth in a mouse model of achondroplasia. We thus demonstrate a ligand-trap concept of targeting the cartilage FGFR3 and delineate a potential therapeutic approach for achondroplasia and other FGFR3-related skeletal dysplasias.

1st Department of Internal Medicine Cardioangiology St Anne's University Hospital Masaryk University 65691 Brno Czech Republic

Central European Institute of Technology Brno University of Technology 61200 Brno Czech Republic

Department of Biology Faculty of Medicine Masaryk University 62500 Brno Czech Republic

Department of Experimental Biology Faculty of Science Masaryk University 62500 Brno Czech Republic

Department of Orthopaedic Surgery University of California Los Angeles Los Angeles CA 90095 USA

Department of Pediatrics Osaka University Graduate School of Medicine 565 0871 Osaka Japan

Institute of Animal Physiology and Genetics Czech Academy of Sciences 60200 Brno Czech Republic

Institute of Medical Science University of Tokyo Tokyo 108 8639 Japan

International Clinical Research Center St Anne's University Hospital 65691 Brno Czech Republic

Networking Research Center on Bioengineering Biomaterials and Nanomedicine LABRET University of Málaga IBIMA BIONAND 29071 Málaga Spain

RIBOMIC Inc Tokyo 108 0071 Japan

References provided by Crossref.org

Specific inhibition of fibroblast growth factor receptor 1 signaling by a DNA aptamer

Achondroplasia: aligning mouse model with human clinical studies shows crucial importance of immediate postnatal start of the therapy

Quantitative and qualitative differences in the activation of a fibroblast growth factor receptor by different FGF ligands

Ligand bias underlies differential signaling of multiple FGFs via FGFR1