An RNA aptamer restores defective bone growth in FGFR3-related skeletal dysplasia in mice

Authors

KIMURA T. BOSÁKOVÁ Michaela NONAKA Y. HRUBA Eva YASUDA K. FUTAKAWA S. KUBOTA T. FAFÍLEK Bohumil GREGOR Tomáš POOVAKULATHU ABRAHAM Sara GOMOLKOVÁ Regína BELASKOVA Silvie PEŠL Martin CSUKASI F. DURAN I. FUJIWARA M. KAVKOVA Michaela ZIKMUND Tomas KAISER Josef BUCHTOVÁ marcela KRAKOW D. NAKAMURA Y. OZONO K. KREJČÍ Pavel

Year of publication 2021
Type Article in Periodical
Magazine / Source Science Translational Medicine
MU Faculty or unit

Faculty of Medicine

Citation
Web https://stm.sciencemag.org/content/13/592/eaba4226
Doi http://dx.doi.org/10.1126/scitranslmed.aba4226
Keywords RNA aptamer; defective bone growth; FGFR3-related skeletal dysplasia; mice
Description 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.
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