Oncogenesis following vector delivery in the fetal mouse appears to be independent of WPRE-presence in vector constructs and supports this animal model for assessment of vector-associated genotoxicity

• Published in: Molecular therapy Vol. 20; no. 9; p. 34
• Main Authors: Nowrouzi, Ali, Cheung, Wing, Li, Tingting, Zhang, Xuegong, Arens, Anne, Paruzynski, Anna, Waddington, Simon N, Osejindu, Emma, Reja, Safia, von Kalle, Christof
• Format: Journal Article
• Language: English
• Published: 01.09.2012
• Subjects: Feline immunodeficiency virus; Lentivirus
• ISSN: 1525-0016; 1525-0024

We previously reported high frequency hepatocellular carcinoma (HCC) development in mice treated with EIAV SMART2/3 based non-primate lentivirus vectors (npLVs) but not with a primate HR'SIN-cPPT-S-FIX-W LV (pLV) vector. Because a truncated form of the X gene carried on the WPRE in the npLV had the potential to be expressed in contrast to pLV where mutations were present to prevent X gene expression it was suggested that the X gene, which in full-length form is known to be involved in HCC, was the cause of oncogenesis. This follow-up report shows WPRE mutagenesis in EIAV npLV does not prevent oncogenesis by this vector and HCC development also occurs at similar frequency using an FIV based npLV. Here we discuss the insertion site profiles of the npLV and pLV vectors and show differences in insertion site selection that are due either to vector insertion preferences by npLV for gene dense regions and highly expressed genes during fetal development or clonal outgrowth as result of npLV mediated genotoxicity. Overall, we observe genes with npLV insertions reduced in expression and, using microarray and Ingenuity pathway analysis (IPA) related genes in HCC networks appear differentially expressed also. Our data indicate the fetal mouse model as useful to determine gene therapy associated genotoxicity and to reveal genes involved in liver oncogenesis.