In vivo genome editing of human haematopoietic stem cells for treatment of blood disorders using mRNA delivery

IF 26.8 1区医学 Q1 ENGINEERING, BIOMEDICAL

Nature Biomedical Engineering Pub Date : 2025-08-12 DOI:10.1038/s41551-025-01480-y

Saijuan Xu, Dan Liang, Qiudao Wang, Yan Cheng, Da Xie, Yang Gui, Haokun Zhang, Changrui Feng, Feiyan Zhao, Wendan Ren, Gongrui Sun, Yang Yang, Lin Li, Yongrong Lai, Bin Fu, Yuming Lu, Zi Jun Wang, Yuxuan Wu

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引用次数: 0

Abstract

Ex vivo autologous haematopoietic stem cell (HSC) gene therapy provides a promising treatment option for haematological disorders. However, current methods involve complex processes and chemotherapeutic conditioning, leading to limited accessibility for treatment and major side effects. Here we develop antibody-free targeted lipid nanoparticles (LNPs) for mRNA delivery to HSCs in vivo, enabling efficient base editing of the γ-globin gene (HBG1/2) promoter target in human HSCs to reactivate fetal haemoglobin in derived erythroid cells. Delivery of ABE8e/sgRNA mRNA with optimized LNPs achieves efficient in vivo base editing of HBG1/2 in transfusion-dependent β-thalassaemia (TDT) patient-derived HSCs engrafted in immunodeficient NCG-X mice, showing restored globin chain balance in erythroid cells. Our research indicates that using LNPs for genome editor delivery achieves efficient editing of endogenous genes of human HSCs. This non-viral delivery system eliminates the need for collecting or mobilizing HSCs, providing a potent and one-time treatment potential for blood disorders such as sickle cell disease and TDT.

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利用mRNA传递治疗血液疾病的人造血干细胞体内基因组编辑

体外自体造血干细胞（HSC）基因治疗为血液病提供了一种有希望的治疗选择。然而，目前的方法涉及复杂的过程和化疗条件，导致治疗的可及性有限和主要的副作用。在这里，我们开发了无抗体的靶向脂质纳米颗粒（LNPs），用于在体内将mRNA递送到造血干细胞，从而能够对人造血干细胞中的γ-珠蛋白基因（HBG1/2）启动子靶点进行有效的碱基编辑，以重新激活衍生红细胞中的胎儿血红蛋白。通过优化LNPs传递ABE8e/sgRNA mRNA，在免疫缺陷的NCG-X小鼠移植的输注依赖性β-地中海贫血（TDT）患者来源的造血干细胞中实现了HBG1/2的高效体内碱基编辑，显示红细胞中球蛋白链平衡恢复。我们的研究表明，使用LNPs进行基因组编辑传递可以实现对人造血干细胞内源基因的高效编辑。这种非病毒输送系统消除了收集或动员造血干细胞的需要，为镰状细胞病和TDT等血液疾病提供了强有力的一次性治疗潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Biomedical Engineering Medicine-Medicine (miscellaneous)

CiteScore

45.30

自引率

1.10%

发文量

138

期刊介绍： Nature Biomedical Engineering is an online-only monthly journal that was launched in January 2017. It aims to publish original research, reviews, and commentary focusing on applied biomedicine and health technology. The journal targets a diverse audience, including life scientists who are involved in developing experimental or computational systems and methods to enhance our understanding of human physiology. It also covers biomedical researchers and engineers who are engaged in designing or optimizing therapies, assays, devices, or procedures for diagnosing or treating diseases. Additionally, clinicians, who make use of research outputs to evaluate patient health or administer therapy in various clinical settings and healthcare contexts, are also part of the target audience.