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

However, current methods involve complex processes and chemotherapeutic conditioning, leading to limited accessibility for treatment and significant 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) promoters target in human HSCs to reactivate fetal hemoglobin 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-thalassemia (TDT) patients-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 harvesting or mobilizing HSCs, providing a potent and one-time treatment potential for blood disorders like sickle cell disease (SCD) and TDT.