Lipid nanoparticle-mediated mRNA delivery to CD34 + cells in rhesus monkeys.

Autor: Kim H; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA., Zenhausern R; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA., Gentry K; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA., Lian L; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA., Huayamares SG; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA., Radmand A; Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA.; Department of Chemical Engineering, Georgia Institute of Technology, Atlanta, GA, USA., Loughrey D; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA., Podilapu AR; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA., Hatit MZC; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA., Ni H; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA., Li A; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA., Shajii A; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA., Peck HE; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA., Han K; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA., Hua X; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA., Jia S; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA., Martinez M; California National Primate Research Center, University of California, Davis, Davis, CA, USA., Lee C; California National Primate Research Center, University of California, Davis, Davis, CA, USA.; Department of Pediatrics, University of California, Davis, Davis, CA, USA., Santangelo PJ; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA., Tarantal A; California National Primate Research Center, University of California, Davis, Davis, CA, USA.; Department of Pediatrics, University of California, Davis, Davis, CA, USA.; Department of Cell Biology and Human Anatomy, University of California, Davis, Davis, CA, USA., Dahlman JE; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA. james.dahlman@emory.edu.
Jazyk: angličtina
Zdroj: Nature biotechnology [Nat Biotechnol] 2024 Nov 22. Date of Electronic Publication: 2024 Nov 22.
DOI: 10.1038/s41587-024-02470-2
Abstrakt: Transplantation of ex vivo engineered hematopoietic stem cells (HSCs) can lead to robust clinical responses but carries risks of adverse events from bone marrow mobilization, chemotherapy conditioning and other factors. HSCs have been modified in vivo using lipid nanoparticles (LNPs) decorated with targeting moieties, which increases manufacturing complexity. Here we screen 105 LNPs without targeting ligands for effective homing to the bone marrow in mouse. We report an LNP named LNP 67 that delivers mRNA to murine HSCs in vivo, primary human HSCs ex vivo and CD34 + cells in rhesus monkeys (Macaca mulatta) in vivo at doses of 0.25 and 0.4 mg kg -1 . Without mobilization and conditioning, LNP 67 can mediate delivery of mRNA to HSCs and their progenitor cells (HSPCs), as well as to the liver in rhesus monkeys, without serum cytokine activation. These data support the hypothesis that in vivo delivery to HSCs and HSPCs in nonhuman primates is feasible without targeting ligands.
Competing Interests: Competing interests: M.Z.C.H., H.N. and J.E.D. have filed a provisional patent related to this manuscript (US patent application number 63/632,354). J.E.D. is an advisor to GV, Readout, Edge Animal Health and Nava Therapeutics and P.J.S. is a cofounder of Tether Therapeutics. None of these companies provided any financial support for this work. The other authors declare no competing interests.
(© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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