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肝细胞向的脂质纳米颗粒用于威尔逊病的全长ATP7BmRNA输送

Yinyu Ma¹, Songli Wang², Zhiwei Guo¹

¹Department of Pharmacology, School of Basic Medical Sciences & Department of Pharmacy, Shanghai Pudong Hospital & State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai 200030, PR China.

Journal of controlled release : official journal of the Controlled Release Society

|October 13, 2025

概括

这项研究引入了一种用于威尔逊病 (WD) 的新型基因疗法,使用脂质纳米粒子 (LNP) 直接将ATP7B mRNA输送到肝细胞,改善铜代谢并降低毒性.

科学领域:

生物技术是生物技术.
遗传学是一个遗传学.
肝病学肝病学是一种肝病学.

背景情况:

威尔逊病 (WD) 是一种由ATP7B基因突变引起的铜代谢遗传性疾病.
目前的WD治疗面临着药物耐药性和副作用等挑战,需要替代疗法.
向肝细胞的mRNA输送为WD提供了一个有前途的治疗策略.

研究的目的:

开发一种针对肝细胞的mRNA治疗系统,用于使用低免疫活性脂质纳米粒子 (LNP) 治疗威尔逊病.
为了增强ATP7BmRNA向肝细胞的传递,同时最大限度地减少非目标效应.
在威尔逊病模型中评估这种新型基因疗法的疗效和安全性.

主要方法:

开发一种针对肝细胞的LNP系统,利用基终结聚乙烯糖醇脂 (OH-PEG) 来降低免疫性.
优化OH-PEG摩尔比率,以提高LNP介导的mRNA在肝细胞中的表达.
在体外评估ATP7B蛋白功能和在体内研究WD模型小鼠,涉及长期干预和安全性评估.

主要成果:

优化OH-PEG比率 (3%) 显著增加肝细胞mRNA表达,并减少非细胞的表达.
试验室研究证实了功能性ATP7B蛋白传递和铜运输.
在WD模型小鼠中,治疗剂量取决于肝脏的铜积累减少了高达72.1%,恢复了铜的平衡,并使质胺活性正常化.
安全性评估显示,生物化学参数,组织病理学,脂质的快速清除得到改善,没有观察到毒性或过敏反应.

结论:

为威尔逊病建立了一个可翻译的基因治疗平台,使用向肝细胞的低免疫活性LNP进行ATP7B mRNA输送.
这种LNP系统通过恢复铜代谢和改善安全性,证明了治疗威尔逊病的潜力.
开发的平台可以适应用于为其他肝脏疾病提供mRNA疗法.

关键词:

ATP7B 是一种携带铜的ATP酶.肝细胞肝细胞肝细胞脂质纳米颗粒是一种纳米粒子.威尔逊病是威尔逊病的一种疾病.mRNA疗法是一种mRNA疗法.

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