Abstract
Fibrosis affects millions of people with cardiac disease. We developed a therapeutic approach to generate transient antifibrotic chimeric antigen receptor (CAR) T cells in vivo by delivering modified messenger RNA (mRNA) in T cell–targeted lipid nanoparticles (LNPs). The efficacy of these in vivo–reprogrammed CAR T cells was evaluated by injecting CD5-targeted LNPs into a mouse model of heart failure. Efficient delivery of modified mRNA encoding the CAR to T lymphocytes was observed, which produced transient, effective CAR T cells in vivo. Antifibrotic CAR T cells exhibited trogocytosis and retained the target antigen as they accumulated in the spleen. Treatment with modified mRNA-targeted LNPs reduced fibrosis and restored cardiac function after injury. In vivo generation of CAR T cells may hold promise as a therapeutic platform to treat various diseases.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adoptive Transfer
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Animals
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CD5 Antigens / immunology
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Cell Engineering*
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Endopeptidases / immunology*
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Endopeptidases / metabolism
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Fibroblasts / immunology
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Fibroblasts / pathology
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Fibrosis / therapy
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HEK293 Cells
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Heart Diseases / pathology
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Heart Diseases / therapy*
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Heart Failure / therapy
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Humans
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Immunotherapy, Adoptive*
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Liposomes*
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Male
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Membrane Proteins / immunology*
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Myocardium / pathology
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Nanoparticles*
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RNA, Messenger / genetics
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Receptors, Chimeric Antigen / genetics
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Receptors, Chimeric Antigen / immunology*
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Receptors, Chimeric Antigen / metabolism
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Spleen / immunology
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T-Lymphocytes / immunology*
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Trogocytosis
Substances
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CD5 Antigens
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Lipid Nanoparticles
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Liposomes
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Membrane Proteins
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RNA, Messenger
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Receptors, Chimeric Antigen
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Endopeptidases
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fibroblast activation protein alpha