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Kimura, T. Bosakova, M. Nonaka, Y. Hruba, E. Yasuda, K. Futakawa, S. Kubota, T. Fafilek, B. Gregor, T. Abraham, S.P. Gomolkova, R Belaskova, S., Pesl M.b, c, f,Csukasi F.g, h,Duran I.g, h,Fujiwara, M. Kavkova, M. Zikmund, T. Kaiser, J. Buchtova, M. Krakow, D. Nakamura, Y. Ozono, K. Krejci, P.
Original Title
An RNA aptamer restores defective bone growth in FGFR3-related skeletal dysplasia in mice
Type
journal article in Web of Science
Language
English
Original Abstract
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.
Keywords
NATRIURETIC-PEPTIDE RESISTANCE; FACTOR RECEPTOR-3; CHONDROCYTE PROLIFERATION; TALL STATURE; FGFR3; ACHONDROPLASIA; MUTATION; RESCUES; HYPOCHONDROPLASIA; PREVALENCE
Authors
Kimura, T.; Bosakova, M.; Nonaka, Y.; Hruba, E.; Yasuda, K.; Futakawa, S.; Kubota, T.; Fafilek, B.; Gregor, T.; Abraham, S.P.; Gomolkova, R; Belaskova, S., Pesl M.b, c, f,Csukasi F.g, h,Duran I.g, h,Fujiwara, M.; Kavkova, M.; Zikmund, T.; Kaiser, J.; Buchtova, M.; Krakow, D.; Nakamura, Y.; Ozono, K.; Krejci, P.
Released
5. 5. 2021
Publisher
AMER ASSOC ADVANCEMENT SCIENCE
Location
WASHINGTON
ISBN
1946-6242
Periodical
Science Translational Medicine
Year of study
13
Number
592
State
United States of America
Pages from
eaba4226-1
Pages to
eaba422-14
Pages count
14
URL
https://www.science.org/doi/10.1126/scitranslmed.aba4226