Bone-marrow-homing lipid nanoparticles for genome editing in diseased and malignant haematopoietic stem cells

Xizhen Lian; Sumanta Chatterjee; Yehui Sun; Sean A. Dilliard; Stephen Moore; Yufen Xiao; Xiaoyan Bian; Kohki Yamada; Yun Chieh Sung; Rachel M. Levine; Kalin Mayberry; Samuel John; Xiaoye Liu; Caroline Smith; Lindsay T. Johnson; Xu Wang; Cheng Cheng Zhang; David R. Liu; Gregory A. Newby; Mitchell J. Weiss; Jonathan S. Yen; Daniel J. Siegwart

doi:10.1038/s41565-024-01680-8

Bone-marrow-homing lipid nanoparticles for genome editing in diseased and malignant haematopoietic stem cells

Xizhen Lian, Sumanta Chatterjee, Yehui Sun, Sean A. Dilliard, Stephen Moore, Yufen Xiao, Xiaoyan Bian, Kohki Yamada, Yun Chieh Sung, Rachel M. Levine, Kalin Mayberry, Samuel John, Xiaoye Liu, Caroline Smith, Lindsay T. Johnson, Xu Wang, Cheng Cheng Zhang, David R. Liu, Gregory A. Newby, Mitchell J. WeissJonathan S. Yen, Daniel J. Siegwart

School of Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	1409-1417
Number of pages	9
Journal	Nature Nanotechnology
Volume	19
Issue number	9
DOIs	https://doi.org/10.1038/s41565-024-01680-8
State	Published - Sep 2024

ASJC Scopus subject areas

Bioengineering
Atomic and Molecular Physics, and Optics
Biomedical Engineering
General Materials Science
Condensed Matter Physics
Electrical and Electronic Engineering

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10.1038/s41565-024-01680-8

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Lian, X., Chatterjee, S., Sun, Y., Dilliard, S. A., Moore, S., Xiao, Y., Bian, X., Yamada, K., Sung, Y. C., Levine, R. M., Mayberry, K., John, S., Liu, X., Smith, C., Johnson, L. T., Wang, X., Zhang, C. C., Liu, D. R., Newby, G. A., ... Siegwart, D. J. (2024). Bone-marrow-homing lipid nanoparticles for genome editing in diseased and malignant haematopoietic stem cells. Nature Nanotechnology, 19(9), 1409-1417. https://doi.org/10.1038/s41565-024-01680-8

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 & Siegwart, DJ 2024, 'Bone-marrow-homing lipid nanoparticles for genome editing in diseased and malignant haematopoietic stem cells', Nature Nanotechnology, vol. 19, no. 9, pp. 1409-1417. https://doi.org/10.1038/s41565-024-01680-8

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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.",

author = "Xizhen Lian and Sumanta Chatterjee and Yehui Sun and Dilliard, {Sean A.} and Stephen Moore and Yufen Xiao and Xiaoyan Bian and Kohki Yamada and Sung, {Yun Chieh} and Levine, {Rachel M.} and Kalin Mayberry and Samuel John and Xiaoye Liu and Caroline Smith and Johnson, {Lindsay T.} and Xu Wang and Zhang, {Cheng Cheng} and Liu, {David R.} and Newby, {Gregory A.} and Weiss, {Mitchell J.} and Yen, {Jonathan S.} and Siegwart, {Daniel J.}",

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AU - Xiao, Yufen

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AU - Siegwart, Daniel J.

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Bone-marrow-homing lipid nanoparticles for genome editing in diseased and malignant haematopoietic stem cells

Abstract

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