PDF(Pubmed)
Abstract：
Hereditary tyrosinemia type 1 is an inborn error of amino acid metabolism characterized by deficiency of fumarylacetoacetate hydrolase (FAH). Only limited treatment options (e.g., oral nitisinone) are available. Patients must adhere to a strict diet and face a life-long risk of complications, including liver cancer and progressive neurocognitive decline. There is a tremendous need for innovative therapies that standardize metabolite levels and promise normal development. Here, we describe an mRNA-based therapeutic approach that rescues Fah-deficient mice, a well-established tyrosinemia model. Repeated intravenous or intramuscular administration of lipid nanoparticle-formulated human FAH mRNA resulted in FAH protein synthesis in deficient mouse livers, stabilized body weight, normalized pathologic increases in metabolites after nitisinone withdrawal, and prevented early death. Dose reduction and extended injection intervals proved therapeutically effective. These results provide proof of concept for an mRNA-based therapeutic approach to treating hereditary tyrosinemia type 1 that is superior to the standard of care.
摘要：
1型遗传性酪氨酸血症是一种先天性氨基酸代谢错误，其特征是富马酸乙酰乙酸水解酶（FAH）缺乏。只有有限的治疗选择(例如，口服尼替辛酮）可用。患者必须坚持严格的饮食，并面临终身并发症的风险，包括肝癌和进行性神经认知能力下降。对于标准化代谢物水平并承诺正常发育的创新疗法存在巨大需求。这里,我们描述了一种基于mRNA的治疗方法，可以拯救Fah缺陷小鼠，一个完善的酪氨酸血症模型。重复静脉内或肌内施用脂质纳米颗粒配制的人FAHmRNA导致缺陷小鼠肝脏中FAH蛋白合成,稳定的体重，Nitisinone戒断后代谢物的正常病理增加，防止过早死亡。剂量减少和延长注射间隔证明是治疗有效的。这些结果为基于mRNA的治疗1型遗传性酪氨酸血症的治疗方法提供了概念证明，该方法优于护理标准。
