{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:57:43Z","timestamp":1792461463193,"version":"4.5.0"},"reference-count":46,"publisher":"SAGE Publications","issue":"11-12","license":[{"start":{"date-parts":[[2024,6,1]],"date-time":"2024-06-01T00:00:00Z","timestamp":1717200000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,6,1]],"date-time":"2024-06-01T00:00:00Z","timestamp":1717200000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2024,6]]},"abstract":"<jats:p>\n                    The ongoing advancements in CRISPR-Cas technologies can significantly accelerate the preclinical development of both\n                    <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">ex vivo<\/jats:italic>\n                    organ genome-editing therapeutics. One of the promising applications is to genetically modify donor organs prior to implantation. The implantation of optimized donor organs with long-lasting immunomodulatory capacity holds promise for reducing the need for lifelong potent whole-body immunosuppression in recipients. However, assessing genome-targeting interventions in a clinically relevant manner prior to clinical trials remains a major challenge owing to the limited modalities available. This study introduces a novel platform for testing genome editing in human lungs\n                    <jats:italic toggle=\"yes\">ex vivo<\/jats:italic>\n                    , effectively simulating preimplantation genetic engineering of donor organs. We identified gene regulatory elements whose disruption via Cas nucleases led to the upregulation of the immunomodulatory gene interleukin 10 (\n                    <jats:italic toggle=\"yes\">IL-10)<\/jats:italic>\n                    . We combined this approach with adenoviral vector-mediated\n                    <jats:italic toggle=\"yes\">IL-10<\/jats:italic>\n                    delivery to create favorable kinetics for early (immediate postimplantation) graft immunomodulation. Using\n                    <jats:italic toggle=\"yes\">ex vivo<\/jats:italic>\n                    organ machine perfusion and precision-cut tissue slice technology, we demonstrated the feasibility of evaluating CRISPR genome editing in human lungs. To overcome the assessment limitations in\n                    <jats:italic toggle=\"yes\">ex vivo<\/jats:italic>\n                    perfused human organs, we conducted an\n                    <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                    rodent study and demonstrated both early gene induction and sustained editing of the lung. Collectively, our findings lay the groundwork for a first-in-human-organ study to overcome the current translational barriers of genome-targeting therapeutics.\n                  <\/jats:p>","DOI":"10.1089\/hum.2023.223","type":"journal-article","created":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T13:06:06Z","timestamp":1715173566000},"page":"374-387","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":12,"title":["CRISPR-Cas Genome Editing in\n                    <i>Ex Vivo<\/i>\n                    Human Lungs to Rewire the Translational Path of Genome-Targeting Therapeutics"],"prefix":"10.1177","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1007-9587","authenticated-orcid":false,"given":"Kumi","family":"Mesaki","sequence":"first","affiliation":[{"name":"Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada"},{"name":"Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruchika","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Juvet","sequence":"additional","affiliation":[{"name":"Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada"},{"name":"Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada"},{"name":"Division of Respirology, Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Yeung","sequence":"additional","affiliation":[{"name":"Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada"},{"name":"Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada"},{"name":"Division of Thoracic Surgery, Department of Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zehong","family":"Guan","sequence":"additional","affiliation":[{"name":"Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akhi","family":"Akhter","sequence":"additional","affiliation":[{"name":"Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Yao","sequence":"additional","affiliation":[{"name":"Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron","family":"Dickie","sequence":"additional","affiliation":[{"name":"Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henna","family":"Mangat","sequence":"additional","affiliation":[{"name":"Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aizhou","family":"Wang","sequence":"additional","affiliation":[{"name":"Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin W.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada"},{"name":"Department of Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Mariscal","sequence":"additional","affiliation":[{"name":"Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jim","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada"},{"name":"Translation Medicine Program, the Hospital for Sick Children, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan R.","family":"Davidson","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada"},{"name":"Department of Molecular Genetics, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin P.","family":"Kleinstiver","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA"},{"name":"Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA"},{"name":"Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo","family":"Cypel","sequence":"additional","affiliation":[{"name":"Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada"},{"name":"Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyao","family":"Liu","sequence":"additional","affiliation":[{"name":"Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada"},{"name":"Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada"},{"name":"Division of Thoracic Surgery, Department of Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaf","family":"Keshavjee","sequence":"additional","affiliation":[{"name":"Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada"},{"name":"Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada"},{"name":"Division of Thoracic Surgery, Department of Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, 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