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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.

References

  1. Laurenti, E. & Gottgens, B. From haematopoietic stem cells to complex differentiation landscapes. Nature 553, 418–426 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bauer, T. R. Jr. et al. Correction of the disease phenotype in canine leukocyte adhesion deficiency using ex vivo hematopoietic stem cell gene therapy. Blood 108, 3313–3320 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Blaese, R. M. et al. T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years. Science 270, 475–480 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Boztug, K. et al. Stem-cell gene therapy for the Wiskott-Aldrich syndrome. N. Engl. J. Med. 363, 1918–1927 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cowan, M. J. et al. Early outcome of a phase I/II clinical trial (NCT03538899) of gene-corrected autologous CD34+ hematopoietic cells and low-exposure busulfan in newly diagnosed patients with Artemis-deficient severe combined immunodeficiency (ART-SCID). Biol. Blood Marrow Transpl. 26, S88–S89 (2020).

    Article  Google Scholar 

  6. Gaspar, H. B. et al. Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet 364, 2181–2187 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Kanter, J. et al. Biologic and clinical efficacy of LentiGlobin for sickle cell disease. N. Engl. J. Med. 386, 617–628 (2022).

    Article  CAS  PubMed  Google Scholar 

  8. Kohn, L. A. & Kohn, D. B. Gene therapies for primary immune deficiencies. Front. Immunol. 12, 648951 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kondo, M. et al. Biology of hematopoietic stem cells and progenitors: implications for clinical application. Annu Rev. Immunol. 21, 759–806 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Locatelli, F. et al. Betibeglogene autotemcel gene therapy for non-β0/β0 genotype β-thalassemia. N. Engl. J. Med. 386, 415–427 (2022).

    Article  CAS  PubMed  Google Scholar 

  11. Malech, H. L. et al. Prolonged production of NADPH oxidase-corrected granulocytes after gene therapy of chronic granulomatous disease. Proc. Natl Acad. Sci. USA 94, 12133–12138 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Morgan, R. A., Gray, D., Lomova, A. & Kohn, D. B. Hematopoietic stem cell gene therapy: progress and lessons learned. Cell Stem Cell 21, 574–590 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sago, C. D. et al. Nanoparticles that deliver RNA to bone marrow identified by in vivo directed evolution. J. Am. Chem. Soc. 140, 17095–17105 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shi, D., Toyonaga, S. & Anderson, D. G. In vivo RNA delivery to hematopoietic stem and progenitor cells via targeted lipid nanoparticles. Nano Lett. 23, 2938–2944 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sou, K., Goins, B., Oyajobi, B. O., Travi, B. L. & Phillips, W. T. Bone marrow-targeted liposomal carriers. Expert Opin. Drug Deliv. 8, 317–328 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sou, K., Klipper, R., Goins, B., Tsuchida, E. & Phillips, W. T. Circulation kinetics and organ distribution of Hb-vesicles developed as a red blood cell substitute. J. Pharmacol. Exp. Ther. 312, 702–709 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Xue, L. et al. Rational design of bisphosphonate lipid-like materials for mRNA delivery to the bone microenvironment. J. Am. Chem. Soc. 144, 9926–9937 (2022).

    Article  CAS  PubMed  Google Scholar 

  18. Boulais, P. E. & Frenette, P. S. Making sense of hematopoietic stem cell niches. Blood 125, 2621–2629 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ikonomi, N., Kuhlwein, S. D., Schwab, J. D. & Kestler, H. A. Awakening the HSC: dynamic modeling of HSC maintenance unravels regulation of the TP53 pathway and quiescence. Front. Physiol. 11, 848 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Li, J. Quiescence regulators for hematopoietic stem cell. Exp. Hematol. 39, 511–520 (2011).

    Article  PubMed  Google Scholar 

  21. Man, Y., Yao, X., Yang, T. & Wang, Y. Hematopoietic stem cell niche during homeostasis, malignancy, and bone marrow transplantation. Front. Cell Dev. Biol. 9, 621214 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Nakamura-Ishizu, A., Takizawa, H. & Suda, T. The analysis, roles and regulation of quiescence in hematopoietic stem cells. Development 141, 4656–4666 (2014).

    Article  CAS  PubMed  Google Scholar 

  23. Eppert, K. et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nat. Med. 17, 1086–1093 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648 (1994).

    Article  CAS  PubMed  Google Scholar 

  25. Mandal, T., Beck, M., Kirsten, N., Linden, M. & Buske, C. Targeting murine leukemic stem cells by antibody functionalized mesoporous silica nanoparticles. Sci. Rep. 8, 989 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Pei, S. & Jordan, C. T. How close are we to targeting the leukemia stem cell? Best Pract. Res. Clin. Haematol. 25, 415–418 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Li, C. et al. Prophylactic in vivo hematopoietic stem cell gene therapy with an immune checkpoint inhibitor reverses tumor growth in syngeneic mouse tumor models. Cancer Res. 80, 549–560 (2020).

    Article  CAS  PubMed  Google Scholar 

  28. Li, C. et al. In vivo HSPC gene therapy with base editors allows for efficient reactivation of fetal globin in beta-YAC mice. Blood Adv. 5, 1122–1135 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Li, C. et al. In vivo HSC gene therapy using a bi-modular HDAd5/35++ vector cures sickle cell disease in a mouse model. Mol. Ther. 29, 822–837 (2021).

    Article  CAS  PubMed  Google Scholar 

  30. Li, C. et al. Safe and efficient in vivo hematopoietic stem cell transduction in nonhuman primates using HDAd5/35++ vectors. Mol. Ther. Methods Clin. Dev. 24, 127–141 (2022).

    Article  PubMed  Google Scholar 

  31. Psatha, N. et al. Enhanced HbF reactivation by multiplex mutagenesis of thalassemic CD34+ cells in vitro and in vivo. Blood 138, 1540–1553 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Muruve, D. A., Barnes, M. J., Stillman, I. E. & Libermann, T. A. Adenoviral gene therapy leads to rapid induction of multiple chemokines and acute neutrophil-dependent hepatic injury in vivo. Hum. Gene Ther. 10, 965–976 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Sweeney, C. L. & De Ravin, S. S. The promise of in vivo HSC prime editing. Blood 141, 2039–2040 (2023).

    Article  CAS  PubMed  Google Scholar 

  34. Worgall, S., Wolff, G., Falck-Pedersen, E. & Crystal, R. G. Innate immune mechanisms dominate elimination of adenoviral vectors following in vivo administration. Hum. Gene Ther. 8, 37–44 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Lek, A. et al. Death after high-dose rAAV9 gene therapy in a patient with Duchenne’s muscular dystrophy. N. Engl. J. Med. 389, 1203–1210 (2023).

    Article  CAS  PubMed  Google Scholar 

  36. Hou, X., Zaks, T., Langer, R. & Dong, Y. Lipid nanoparticles for mRNA delivery. Nat. Rev. Mater. 6, 1078–1094 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Cheng, Q. et al. Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR-Cas gene editing. Nat. Nanotechnol. 15, 313–320 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dilliard, S. A., Cheng, Q. & Siegwart, D. J. On the mechanism of tissue-specific mRNA delivery by selective organ targeting nanoparticles. Proc. Natl Acad. Sci. USA 118, e2109256118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dilliard, S. A. & Siegwart, D. J. Passive, active and endogenous organ-targeted lipid and polymer nanoparticles for delivery of genetic drugs. Nat. Rev. Mater. 8, 282–300 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Farbiak, L. et al. All-in-one dendrimer-based lipid nanoparticles enable precise HDR-mediated gene editing in vivo. Adv. Mater. 33, e2006619 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Liu, S. et al. Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR-Cas gene editing. Nat. Mater. 20, 701–710 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Liu, S. et al. Zwitterionic phospholipidation of cationic polymers facilitates systemic mRNA delivery to spleen and lymph nodes. J. Am. Chem. Soc. 143, 21321–21330 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wang, X. et al. Preparation of selective organ-targeting (SORT) lipid nanoparticles (LNPs) using multiple technical methods for tissue-specific mRNA delivery. Nat. Protoc. 18, 265–291 (2023).

    Article  CAS  PubMed  Google Scholar 

  44. Wei, T., Cheng, Q., Min, Y. L., Olson, E. N. & Siegwart, D. J. Systemic nanoparticle delivery of CRISPR-Cas9 ribonucleoproteins for effective tissue specific genome editing. Nat. Commun. 11, 3232 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhang, D. et al. Enhancing CRISPR/Cas gene editing through modulating cellular mechanical properties for cancer therapy. Nat. Nanotechnol. 17, 777–787 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wu, L. C. et al. Correction of sickle cell disease by homologous recombination in embryonic stem cells. Blood 108, 1183–1188 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Metais, J. Y. et al. Genome editing of HBG1 and HBG2 to induce fetal hemoglobin. Blood Adv. 3, 3379–3392 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Newby, G. A. et al. Base editing of haematopoietic stem cells rescues sickle cell disease in mice. Nature 595, 295–302 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Stavropoulou, V., Peters, A. & Schwaller, J. Aggressive leukemia driven by MLL-AF9. Mol. Cell Oncol. 5, e1241854 (2018).

    Article  PubMed  Google Scholar 

  50. Hou, X. et al. Vitamin lipid nanoparticles enable adoptive macrophage transfer for the treatment of multidrug-resistant bacterial sepsis. Nat. Nanotechnol. 15, 41–46 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Morales-Tenorio, M. et al. Potential pharmacological strategies targeting the Niemann-Pick C1 receptor and Ebola virus glycoprotein interaction. Eur. J. Med. Chem. 223, 113654 (2021).

    Article  CAS  PubMed  Google Scholar 

  52. Zuo, Y. et al. Controlled delivery of a neurotransmitter-agonist conjugate for functional recovery after severe spinal cord injury. Nat. Nanotechnol. 18, 1230–1240 (2023).

    Article  CAS  PubMed  Google Scholar 

  53. Boike, L., Henning, N. J. & Nomura, D. K. Advances in covalent drug discovery. Nat. Rev. Drug Discov. 21, 881–898 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhou, K. et al. Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model. Proc. Natl Acad. Sci. USA 113, 520–525 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Madisen, L. et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat. Neurosci. 13, 133–140 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Akinc, A. et al. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol. Ther. 18, 1357–1364 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kim, M. et al. Engineered ionizable lipid nanoparticles for targeted delivery of RNA therapeutics into different types of cells in the liver. Sci. Adv. 7, eabf4398 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Enache, O. M. et al. Cas9 activates the p53 pathway and selects for p53-inactivating mutations. Nat. Genet. 52, 662–668 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Haapaniemi, E., Botla, S., Persson, J., Schmierer, B. & Taipale, J. CRISPR-Cas9 genome editing induces a p53-mediated DNA damage response. Nat. Med. 24, 927–930 (2018).

    Article  CAS  PubMed  Google Scholar 

  60. Leibowitz, M. L. et al. Chromothripsis as an on-target consequence of CRISPR-Cas9 genome editing. Nat. Genet. 53, 895–905 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Mayuranathan, T. et al. Potent and uniform fetal hemoglobin induction via base editing. Nat. Genet. 55, 1210–1220 (2023).

  62. Zuccaro, M. V. et al. Allele-specific chromosome removal after Cas9 cleavage in human embryos. Cell 183, 1650–1664e1615 (2020).

    Article  CAS  PubMed  Google Scholar 

  63. Anzalone, A. V. et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature 576, 149–157 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Miller, S. M. et al. Continuous evolution of SpCas9 variants compatible with non-G PAMs. Nat. Biotechnol. 38, 471–481 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Richter, M. F. et al. Phage-assisted evolution of an adenine base editor with improved Cas domain compatibility and activity. Nat. Biotechnol. 38, 883–891 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Breda, L. et al. In vivo hematopoietic stem cell modification by mRNA delivery. Science 381, 436–443 (2023).

    Article  CAS  PubMed  Google Scholar 

  67. Marschalek, R. MLL leukemia and future treatment strategies. Arch. Pharm. 348, 221–228 (2015).

    Article  CAS  Google Scholar 

  68. Stavropoulou, V. et al. MLL-AF9 expression in hematopoietic stem cells drives a highly invasive AML expressing EMT-related genes linked to poor outcome. Cancer Cell 30, 43–58 (2016).

    Article  CAS  PubMed  Google Scholar 

  69. Kang, X. et al. The ITIM-containing receptor LAIR1 is essential for acute myeloid leukaemia development. Nat. Cell Biol. 17, 665–677 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wu, G. et al. LILRB3 supports acute myeloid leukemia development and regulates T-cell antitumor immune responses through the TRAF2–cFLIP–NF-κB signaling axis. Nat. Cancer 2, 1170–1184 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Zheng, J. et al. Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development. Nature 485, 656–660 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Itskovich, S. S. et al. MBNL1 regulates essential alternative RNA splicing patterns in MLL-rearranged leukemia. Nat. Commun. 11, 2369 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Barreto, I. V. et al. Leukemic stem cell: a mini-review on clinical perspectives. Front. Oncol. 12, 931050 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Clement, K. et al. CRISPResso2 provides accurate and rapid genome editing sequence analysis. Nat. Biotechnol. 37, 224–226 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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