1. Bone-marrow-homing lipid nanoparticles for genome editing in diseased and malignant haematopoietic stem cells.
- Author
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Lian X, Chatterjee S, Sun Y, Dilliard SA, Moore S, Xiao Y, Bian X, Yamada K, Sung YC, Levine RM, Mayberry K, John S, Liu X, Smith C, Johnson LT, Wang X, Zhang CC, Liu DR, Newby GA, Weiss MJ, Yen JS, and Siegwart DJ
- Abstract
Therapeutic genome editing of haematopoietic stem cells (HSCs) would provide long-lasting treatments for multiple diseases. However, the in vivo delivery of genetic medicines to HSCs remains challenging, especially in diseased and malignant settings. Here we report on a series of bone-marrow-homing lipid nanoparticles that deliver mRNA to a broad group of at least 14 unique cell types in the bone marrow, including healthy and diseased HSCs, leukaemic stem cells, B cells, T cells, macrophages and leukaemia cells. CRISPR/Cas and base editing is achieved in a mouse model expressing human sickle cell disease phenotypes for potential foetal haemoglobin reactivation and conversion from sickle to non-sickle alleles. Bone-marrow-homing lipid nanoparticles were also able to achieve Cre-recombinase-mediated genetic deletion in bone-marrow-engrafted leukaemic stem cells and leukaemia cells. We show evidence that diverse cell types in the bone marrow niche can be edited using bone-marrow-homing lipid nanoparticles., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2024
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