The highly prevalent metabolic dysfunction-associated steatohepatitis (MASH) is associated with liver steatosis, inflammation, and hepatocyte injury, which can lead to fibrosis and may progress to hepatocellular carcinoma and death. New treatment modalities such as gene therapy may be transformative for MASH patients. Here, we describe that one-time intramuscular administration of adeno-associated viral vectors of serotype 1 (AAV1) encoding native fibroblast growth factor 21 (FGF21), a key metabolic regulator, resulted in sustained increased circulating levels of the factor, which mediated long-term (>1 year) MASH and hepatic fibrosis reversion and halted development of liver tumors in obese male and female mouse models. AAV1-FGF21 treatment also counteracted obesity, adiposity, and insulin resistance, which are significant drivers of MASH. Scale-up to large animals successfully resulted in safe skeletal muscle biodistribution and biological activity in key metabolic tissues. Moreover, as a step toward the clinic, circulating FGF21 levels were characterized in obese, insulin-resistant and MASH patients. Overall, these results underscore the potential of the muscle-directed AAV1-FGF21 gene therapy to treat MASH and support its clinical translation.

中文翻译：

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骨骼肌定向 FGF21 基因治疗逆转代谢功能障碍相关脂肪性肝炎


高度普遍的代谢功能障碍相关脂肪性肝炎 （MASH） 与肝脂肪变性、炎症和肝细胞损伤有关，可导致纤维化，并可能发展为肝细胞癌和死亡。新的治疗方式（例如基因治疗）可能会对 MASH 患者产生变革性影响。在这里，我们描述了一次性肌肉注射编码天然成纤维细胞生长因子 21 （FGF21） 的血清型 1 （AAV1） 腺相关病毒载体，一种关键代谢调节因子，导致该因子的循环水平持续升高，这介导了长期 （>1 年） MASH 和肝纤维化逆转，并阻止了肥胖雄性和雌性小鼠模型中肝肿瘤的发展。AAV1-FGF21 治疗还抵消了肥胖、肥胖和胰岛素抵抗，这些都是 MASH 的重要驱动因素。扩大到大型动物成功地在关键代谢组织中实现了安全的骨骼肌生物分布和生物活性。此外，作为迈向临床的一步，在肥胖、胰岛素抵抗和 MASH 患者中表征了循环 FGF21 水平。总体而言，这些结果强调了肌肉定向 AAV1-FGF21 基因疗法治疗 MASH 并支持其临床转化的潜力。