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The Fetal Mouse Is a Sensitive Genotoxicity Model That Exposes Lentiviral-associated Mutagenesis Resulting in Liver Oncogenesis |
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| Authors: | Ali Nowrouzi Wing T Cheung Tingting Li Xuegong Zhang Anne Arens Anna Paruzynski Simon N Waddington Emma Osejindu Safia Reja Christof von Kalle Yoahe Wang Faisal Al-Allaf Lisa Gregory Matthew Themis Maxine Holder Niraja Dighe Alaine Ruthe Suzanne MK Buckley Mike Themis |
| Affiliation: | 1. National Centre for Tumorigenesis (NCT), Heidelberg Technology park TP4, Heidelberg, Germany;2. Gene Therapy Research Group, Section of Cell and Molecular Biology, Imperial College, London, UK;3. Bioinformatics Division, TNLIST and Department of Automation, Tsinghua University, Beijing, China;4. Peking University Medical School, Peking, China;5. Institute for Women''s Health, University College London, London, UK;6. Brunel Institute for Cancer Genetics and Pharmacogenomics, Division of Biosciences, Brunel University, Uxbridge, UK;7. Division of Experimental Hematology, Cincinnati Children''s Hospital Medical Center, Cincinnati, Ohio, USA;8. Cancer Research UK, Queen Mary''s School of Medicine & Dentistry at Barts & The London John Vane Science Centre, London, UK;9. Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia;10. Molecular Immunology Unit, Institute of Child Health, London, UK;11. Apoptosis and Proliferation Control Laboratory, Cancer Research UK, London, UK;12. Stem Cell & Neurotherapies Group, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK;13. San Raffaele Telethon Institute for Gene Therapy, HSR-TIGET, Safety of Gene Therapy and Insertional Mutagenesis Research Unit, Milan, Italy;14. Wellcome Trust Sanger Institute, Cambridge, UK |
| Abstract: | Genotoxicity models are extremely important to assess retroviral vector biosafety before gene therapy. We have developed an in utero model that demonstrates that hepatocellular carcinoma (HCC) development is restricted to mice receiving nonprimate (np) lentiviral vectors (LV) and does not occur when a primate (p) LV is used regardless of woodchuck post-translation regulatory element (WPRE) mutations to prevent truncated X gene expression. Analysis of 839 npLV and 244 pLV integrations in the liver genomes of vector-treated mice revealed clear differences between vector insertions in gene dense regions and highly expressed genes, suggestive of vector preference for insertion or clonal outgrowth. In npLV-associated clonal tumors, 56% of insertions occurred in oncogenes or genes associated with oncogenesis or tumor suppression and surprisingly, most genes examined (11/12) had reduced expression as compared with control livers and tumors. Two examples of vector-inserted genes were the Park 7 oncogene and Uvrag tumor suppressor gene. Both these genes and their known interactive partners had differential expression profiles. Interactive partners were assigned to networks specific to liver disease and HCC via ingenuity pathway analysis. The fetal mouse model not only exposes the genotoxic potential of vectors intended for gene therapy but can also reveal genes associated with liver oncogenesis. |
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