Fragile X syndrome (FXS) is a genetic condition due to a mutation in the fragile X messenger ribonucleoprotein 1 (FMR1) gene that causes a range of developmental problems, including features of autism spectrum disorder (ASD). Metformin, an antidiabetic FDA-approved drug, has emerged as a candidate drug for the targeted treatment of FXS based on animal studies, including a study in which metformin treatment corrected core ASD phenotypes in Fmr1 knockout mice. A new study in PNAS now shows that early-in-life metformin intervention is effective in treating FXS pathophysiology in Fmr1 KO mice. Metformin treatment from birth corrected both MAPK/ERK and mTORC1 signaling pathways, which show increased signaling in FXS. This reduction in signaling cascades corrected behavioral deficits and normalized elevated levels of specific synaptic FMRP-binding targets, which was not observed in previous studies using adult Fmr1 KO mice. Altogether, these results suggest that metformin administration should be started early in patients with FXS, as soon as the condition is diagnosed.

Original reference: Choi, J.H. et al. Proc. Natl. Acad. Sci. USA 121, e2407546121 (2024)

脆性 X 综合征 (FXS) 是一种由脆性 X 信使核糖核蛋白 1 (FMR1) 基因突变引起的遗传性疾病，会导致一系列发育问题，包括自闭症谱系障碍 (ASD) 的特征。二甲双胍是 FDA 批准的抗糖尿病药物，基于动物研究，已成为 FXS 靶向治疗的候选药物，其中包括一项二甲双胍治疗纠正Fmr1敲除小鼠的核心 ASD 表型的研究。 PNAS的一项新研究现在表明，生命早期的二甲双胍干预可有效治疗Fmr1 KO 小鼠的 FXS 病理生理学。从出生起接受二甲双胍治疗即可纠正 MAPK/ERK 和 mTORC1 信号通路，这表明 FXS 中的信号传导增强。这种信号级联的减少纠正了行为缺陷，并使特定突触 FMRP 结合靶点的升高水平正常化，这在之前使用成年Fmr1 KO 小鼠的研究中未观察到。总而言之，这些结果表明，FXS 患者一旦确诊，就应尽早开始服用二甲双胍。

原文参考： Choi, JH et al .过程。国家。阿卡德。科学。美国121 ，e2407546121 (2024)