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

Nature Nanotechnology (2024)Cite this article

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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.

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Fig. 1: Discovery and development of BM-homing LNPs.
Fig. 2: tdTom expression in BM cells was activated by Cre mRNA BM-homing LNP delivery.
Fig. 3: Factors that do and do not contribute to BM delivery tropism.
Fig. 4: In vivo genome and base editing of β-globin-disorder-relevant genes in HBBS/S Townes mice.
Fig. 5: tdTom expression in MLL-AF9-driven AML model was activated by BM-homing LNP-mediated editing.

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Data Availability

DNA sequencing files can be accessed at the National Center for Biotechnology Information Sequence Read Archive (NCBI SRA) with accession code PRJNA1082713. Source data are provided with this paper. All other data are available from the corresponding author upon reasonable request.

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Acknowledgements

The research was supported by the National Institutes of Health (NIH), National Institute of Biomedical Imaging and Bioengineering (NIBIB) (R01 5R01EB025192-06) and National Cancer Institute (R01 CA269787-01); the Welch Foundation (I-2123-20220031); and the Cystic Fibrosis Foundation (CFF) (SIEGWA18XX0, SIEGWA21XX0) (to D.J.S). We also acknowledge support from the UTSW Small Animal Imaging Resource (NCI P30CA142543), the UTSW Proteomics Core, NIH (1R01 CA248736) and Leukemia & Lymphoma Society (6629-21) to C.C.Z., NIH (R01HL156647) (to M.J.W.) and the St Jude Children’s Research Hospital Collaborative Research Consortium for Sickle Cell Disease.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Department of Biochemistry, Simmons Comprehensive Cancer Center, Program in Genetic Drug Engineering, The University of Texas Southwestern Medical Center, Dallas, TX, USA

    Xizhen Lian, Sumanta Chatterjee, Yehui Sun, Sean A. Dilliard, Stephen Moore, Yufen Xiao, Xiaoyan Bian, Kohki Yamada, Yun-Chieh Sung, Lindsay T. Johnson, Xu Wang & Daniel J. Siegwart

  2. Department of Hematology, St Jude Children’s Research Hospital, Memphis, TN, USA

    Rachel M. Levine, Kalin Mayberry, Mitchell J. Weiss & Jonathan S. Yen

  3. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Samuel John, Xiaoye Liu, Caroline Smith & Cheng Cheng Zhang

  4. Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA

    David R. Liu

  5. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA

    David R. Liu

  6. Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA

    David R. Liu

  7. Department of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA

    Gregory A. Newby

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  1. Xizhen Lian
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Contributions

X. Lian and D.J.S. conceived and designed the experiments and wrote the manuscript. X. Lian, S.C., Y.S., S.A.D., S.M., Y.X., X.B., K.Y., Y.-C.S., R.M.L., K.M., S.J., X. Liu, C.S., L.T.J., X.W. and G.A.N. performed the experiments. All authors discussed the results and commented on the manuscript. D.J.S. directed the research.

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Correspondence to Daniel J. Siegwart.

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Competing interests

UT Southwestern has filed patent applications on the technologies described in this manuscript with X. Lian and D.J.S. listed as inventors. D.J.S. discloses the following competing interests: ReCode Therapeutics, Signify Bio, Tome Biosciences, Jumble Therapeutics and Pfizer Inc. D.R.L. is a consultant and equity holder of Beam Therapeutics, Prime Medicine, Pairwise Plants, Chroma Medicine and Nvelop Therapeutics, companies that use or deliver gene-editing or epigenome-modulating agents. M.J.W. is a consultant for GlaxoSmithKline, Cellarity, Novartis and Dyne Therapeutics. J.S.Y. is an equity owner of Beam Therapeutics. The remaining authors declare no competing interests.

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Lian, X., Chatterjee, S., Sun, Y. et al. Bone-marrow-homing lipid nanoparticles for genome editing in diseased and malignant haematopoietic stem cells. Nat. Nanotechnol. (2024). https://doi.org/10.1038/s41565-024-01680-8

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