Low-dose infigratinib increases bone growth and corrects growth plate abnormalities in an achondroplasia mouse model.

Autor:	Demuynck B; Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR1163, Université de Paris Cité, Imagine Institute, Paris, France., Flipo J; Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR1163, Université de Paris Cité, Imagine Institute, Paris, France., Kaci N; Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR1163, Université de Paris Cité, Imagine Institute, Paris, France., Dambkowski C; QED Therapeutics, San Francisco, CA 94107, United States., Paull M; QED Therapeutics, San Francisco, CA 94107, United States., Muslimova E; QED Therapeutics, San Francisco, CA 94107, United States., Shah BP; QED Therapeutics, San Francisco, CA 94107, United States., Legeai-Mallet L; Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR1163, Université de Paris Cité, Imagine Institute, Paris, France.
Jazyk:	angličtina
Zdroj:	Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research [J Bone Miner Res] 2024 Jul 23; Vol. 39 (6), pp. 765-774.
DOI:	10.1093/jbmr/zjae051
Abstrakt:	Achondroplasia (ACH), the most common form of disproportionate short stature, is caused by gain-of-function point mutations in fibroblast growth factor receptor 3 (FGFR3). Abnormally elevated activation of FGFR3 modulates chondrocyte proliferation and differentiation via multiple signaling pathways, such as the MAPK pathway. Using a mouse model mimicking ACH (Fgfr3Y367C/+), we have previously shown that daily treatment with infigratinib (BGJ398), a selective and orally bioavailable FGFR1-3 inhibitor, at a dose of 2 mg/kg, significantly increased bone growth. In this study, we investigated the activity of infigratinib administered at substantially lower doses (0.2 and 0.5 mg/kg, given once daily) and using an intermittent dosing regimen (1 mg/kg every 3 days). Following a 15-day treatment period, these low dosages were sufficient to observe significant improvement of clinical hallmarks of ACH such as growth of the axial and appendicular skeleton and skull development. Immunohistological labeling demonstrated the positive impact of infigratinib on chondrocyte differentiation in the cartilage growth plate and the cartilage end plate of the vertebrae. Macroscopic and microcomputed analyses showed enlargement of the foramen magnum area at the skull base, thus improving foramen magnum stenosis, a well-recognized complication in ACH. No changes in FGF23 or phosphorus levels were observed, indicating that the treatment did not modify phosphate homeostasis. This proof-of-concept study demonstrates that infigratinib administered at low doses has the potential to be a safe and effective therapeutic option for children with ACH. (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)
Databáze:	MEDLINE
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