Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature aging disorder without an effective therapeutic regimen. Because of their targetability and influence on gene expression, microRNAs (miRNAs) are attractive therapeutic tools to treat diseases. Here we identified that hsa-miR-59 (miR-59) was markedly upregulated in HGPS patient cells and in multiple tissues of an HGPS mouse model (Lmna^G609G/G609G), which disturbed the interaction between RNAPII and TFIIH, resulting in abnormal expression of cell cycle genes by targeting high-mobility group A family HMGA1 and HMGA2. Functional inhibition of miR-59 alleviated the cellular senescence phenotype of HGPS cells. Treatment with AAV9-mediated anti-miR-59 reduced fibrosis in the quadriceps muscle, heart, and aorta, suppressed epidermal thinning and dermal fat loss, and yielded a 25.5% increase in longevity of Lmna^G609G/G609G mice. These results identify a new strategy for the treatment of HGPS and provide insight into the etiology of HGPS disease.

中文翻译：

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抗 hsa-miR-59 可减轻小鼠 Hutchinson-Gilford 早衰综合征相关的过早衰老

Hutchinson-Gilford 早衰综合征 (HGPS) 是一种致命的早衰症，目前尚无有效的治疗方案。由于它们的靶向性和对基因表达的影响，microRNA (miRNA) 是治疗疾病的有吸引力的治疗工具。在这里，我们发现 hsa-miR-59 (miR-59) 在 HGPS 患者细胞和 HGPS 小鼠模型 ( Lmna ^{G609G / G609G ) 的多个组织中显着上调}), 它扰乱了 RNAPII 和 TFIIH 之间的相互作用, 通过靶向高迁移率组 A 家族 HMGA1 和 HMGA2 导致细胞周期基因的异常表达。miR-59 的功能抑制减轻了 HGPS 细胞的细胞衰老表型。用 AAV9 介导的抗 miR-59 治疗可减少股四头肌、心脏和主动脉的纤维化，抑制表皮变薄和真皮脂肪流失，并使Lmna ^{G609G / G609G}小鼠的寿命延长 25.5%。这些结果确定了治疗 HGPS 的新策略，并提供了对 HGPS 疾病病因学的深入了解。