{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:37:14Z","timestamp":1787027834399,"version":"build-2736575974"},"reference-count":98,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,11,29]],"date-time":"2024-11-29T00:00:00Z","timestamp":1732838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"United Kingdom Medical Research Council Clinician Scientist Fellowship","award":["MR\/T008024\/1"],"award-info":[{"award-number":["MR\/T008024\/1"]}]},{"name":"Moderna Therapeutics","award":["MR\/T008024\/1"],"award-info":[{"award-number":["MR\/T008024\/1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Recently approved adeno-associated viral (AAV) vectors for liver monogenic diseases haemophilia A and B are exemplifying the success of liver-directed viral gene therapy. In parallel, additional gene therapy strategies are rapidly emerging to overcome some inherent AAV limitations, such as the non-persistence of the episomal transgene in the rapidly growing liver and immune response. Viral integrating vectors such as in vivo lentiviral gene therapy and non-viral vectors such as lipid nanoparticles encapsulating mRNA (LNP-mRNA) are rapidly being developed, currently at the preclinical and clinical stages, respectively. Macrophages are the first effector cells of the innate immune response triggered by gene therapy vectors. Macrophage uptake and activation following administration of viral gene therapy and LNP have been reported. In this study, we assessed the biodistribution of AAV, lentiviral, and LNP-mRNA gene therapy following the depletion of tissue macrophages by clodronate pre-treatment in neonatal and juvenile mice. Both neonatal and adult clodronate-treated mice showed a significant increase in lentiviral-transduced hepatocytes. In contrast, clodronate pre-treatment did not modify hepatocyte transduction mediated by hepatotropic AAV8 but reduced LNP-mRNA transfection in neonatal and juvenile animals. These results highlight the importance of age-specific responses in the liver and will have translational applications for gene therapy programs.<\/jats:p>","DOI":"10.3390\/cells13231979","type":"journal-article","created":{"date-parts":[[2024,11,29]],"date-time":"2024-11-29T08:24:14Z","timestamp":1732868654000},"page":"1979","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Macrophage Inhibitor Clodronate Enhances Liver Transduction of Lentiviral but Not Adeno-Associated Viral Vectors or mRNA Lipid Nanoparticles in Neonatal and Juvenile Mice"],"prefix":"10.3390","volume":"13","author":[{"given":"Loukia","family":"Touramanidou","sequence":"first","affiliation":[{"name":"Great Ormond Street Institute of Child Health, University College London, London WC1E 1EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonam","family":"Gurung","sequence":"additional","affiliation":[{"name":"Great Ormond Street Institute of Child Health, University College London, London WC1E 1EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1775-0265","authenticated-orcid":false,"given":"Claudiu A.","family":"Cozmescu","sequence":"additional","affiliation":[{"name":"Great Ormond Street Institute of Child Health, University College London, London WC1E 1EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5450-8801","authenticated-orcid":false,"given":"Dany","family":"Perocheau","sequence":"additional","affiliation":[{"name":"Great Ormond Street Institute of Child Health, University College London, London WC1E 1EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dale","family":"Moulding","sequence":"additional","affiliation":[{"name":"Great Ormond Street Institute of Child Health, University College London, London WC1E 1EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick F.","family":"Finn","sequence":"additional","affiliation":[{"name":"Moderna, Inc., Cambridge, MA 02139, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Frassetto","sequence":"additional","affiliation":[{"name":"Moderna, Inc., Cambridge, MA 02139, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4970-4730","authenticated-orcid":false,"given":"Simon N.","family":"Waddington","sequence":"additional","affiliation":[{"name":"Institute for Women\u2019s Health, University College London, London WC1E 6HX, UK"},{"name":"Wits\/SAMRC Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, University of Witswatersrand, Johannesburg 2193, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9712-6122","authenticated-orcid":false,"given":"Paul","family":"Gissen","sequence":"additional","affiliation":[{"name":"Great Ormond Street Institute of Child Health, University College London, London WC1E 1EH, UK"},{"name":"Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0582-540X","authenticated-orcid":false,"given":"Julien","family":"Baruteau","sequence":"additional","affiliation":[{"name":"Great Ormond Street Institute of Child Health, University College London, London WC1E 1EH, UK"},{"name":"Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1002\/jimd.12609","article-title":"Gene therapy for urea cycle defects: An update from historical perspectives to future prospects","volume":"47","author":"Duff","year":"2023","journal-title":"J. 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