非加替尼低剂量治疗是治疗软骨发育不良的有效策略。

IF 5.9 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Benoit Demuynck, Bhavik P Shah, Franck Mayeux, Laurine Vasseur, Florent Barbault, Jixin Ding, Morgan Paull, Tejaswini Reddi, Elena Muslimova, Laurence Legeai-Mallet
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引用次数: 0

摘要

软骨发育不良是一种罕见的骨骼发育不良的遗传形式,由成纤维细胞生长因子受体3 (FGFR3)的功能获得致病性变异引起。它的特点是不成比例的身材矮小,具有广泛的临床特征。目前,尚无针对软骨发育不良的精确治疗方案。Infigratinib是一种口服生物可利用的FGFR1-3选择性酪氨酸激酶抑制剂,用于软骨发育不全和软骨发育不全。Infigratinib通过抑制FGFR3的磷酸化和减弱两种主要的下游信号通路,直接作用于这两种疾病的病理生理原因。一项2期研究的结果支持了发炎替尼有可能改善软骨发育不全患者的骨生长的概念。我们报告了对炎性替尼治疗软骨发育不全相关性的逐步评估结果:炎性替尼与软骨发育不全相关的FGFR3变异的计算机评估显示有很强的相互作用;在体外,炎性替尼表现出较强的抑制作用;在软骨发育不良小鼠模型(Fgfr3N534K/+)中,消炎替尼显著改善了骨骼生长。这些数据以及在软骨发育不全儿童中进行的2期研究的临床结果为发炎替尼治疗软骨发育不全的发展提供了支持。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Infigratinib low dose therapy is an effective strategy to treat hypochondroplasia.

Hypochondroplasia is a rare genetic form of skeletal dysplasia, caused by gain-of-function pathogenic variants in the fibroblast growth factor receptor 3 (FGFR3). It is characterized by disproportionate short stature and has a wide spectrum of clinical features. Currently, there are no precision therapeutic options approved for hypochondroplasia. Infigratinib is an orally bioavailable FGFR1-3 selective tyrosine kinase inhibitor in development for achondroplasia and hypochondroplasia. Infigratinib acts directly at the source of the pathophysiological cause of both conditions by inhibiting the phosphorylation of FGFR3 and attenuating both main downstream signaling pathways that are involved in the conditions. Results from a Phase 2 study support the concept that infigratinib has a potential to improve bone growth in achondroplasia. We report results of a step-wise evaluation of the therapeutic relevance of infigratinib for hypochondroplasia: in silico assessment of infigratinib with hypochondroplasia associated FGFR3 variants suggest strong interaction; in vitro, infigratinib showed potent inhibitory effect; in a mouse model of hypochondroplasia (Fgfr3N534K/+), infigratinib resulted in significant improvement in skeletal growth. These data in addition to the clinical results from the Phase 2 study conducted in children with achondroplasia provide support for the development of infigratinib in the treatment of hypochondroplasia.

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来源期刊
Journal of Bone and Mineral Research
Journal of Bone and Mineral Research 医学-内分泌学与代谢
CiteScore
11.30
自引率
6.50%
发文量
257
审稿时长
2 months
期刊介绍: The Journal of Bone and Mineral Research (JBMR) publishes highly impactful original manuscripts, reviews, and special articles on basic, translational and clinical investigations relevant to the musculoskeletal system and mineral metabolism. Specifically, the journal is interested in original research on the biology and physiology of skeletal tissues, interdisciplinary research spanning the musculoskeletal and other systems, including but not limited to immunology, hematology, energy metabolism, cancer biology, and neurology, and systems biology topics using large scale “-omics” approaches. The journal welcomes clinical research on the pathophysiology, treatment and prevention of osteoporosis and fractures, as well as sarcopenia, disorders of bone and mineral metabolism, and rare or genetically determined bone diseases.
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