造血
基因组编辑
干细胞
体内
信使核糖核酸
生物
基因组
计算生物学
医学
细胞生物学
基因
遗传学
作者
Saijuan Xu,Dan Liang,Qiudao Wang,Yan Cheng,Da Xie,Gui Yang,Haokun Zhang,Feiyan Zhao,Wendan Ren,Gongrui Sun,Yang Yang,Lin Li,Yongrong Lai,Bin Fu,Yuming Lu,Zijun Wang,Yuxuan Wu
标识
DOI:10.1101/2024.10.28.620445
摘要
Ex vivo autologous hematopoietic stem cells (HSCs) gene therapy provides promising new treatments for hematological disorders. However, current methods involve complex processes and chemotherapeutic conditioning, leading to limited accessibility for treatment and significant side effects. Here, we developed an antibody-free targeted lipid nanoparticles (LNPs) for mRNA delivery to HSCs in vivo, enabling efficient base editing of the HBG target in human HSCs to reactivate fetal hemoglobin in derived erythroid cells. Delivery of ABE8e/sgRNA mRNA with optimized structure LNPs achieves efficient in vivo base editing of HBG in transfusion-dependent β-thalassemia (TDT) patients derived HSCs engrafted in immunodeficient NCG-X mice, showing restored globin chain balance in erythroid cells. Our research indicated that utilizing LNPs for delivery of genome editor achieves efficient editing of endogenous genes of human HSCs. Notably, this non-viral delivery system eliminates the need for harvesting or mobilizing HSCs, providing a potent and one-time treatment potential for blood disorders like sickle cell disease (SCD) and TDT.
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