Production of human clotting Factor IX without toxicity in mice after vascular delivery of a lentiviral vector
Lisa V. Tsui1, 2, Michael Kelly1, 2, Nathalie Zayek1, Virginia Rojas1, Ken Ho1, Ying Ge1, Marina Moskalenko1, Jean Mondesire1, Jennifer Davis1, Melinda Van Roey1, Tom Dull1
& James G. McArthur1
1
Cell Genesys Inc., 342 Lakeside Drive, Foster City CA 94404.
2
Each of these authors contributed equally to the work.
Replication-deficient lentiviral vectors (LV) have been shown to enable the stable genetic modification of multiple cell types in vivo. We demonstrate here that vascular and hepatic delivery of a third-generation HIV-derived lentiviral vector encoding human Factor IX (LV-hFIX) produced potentially therapeutic serum levels of hFIX protein with no vector-mediated local or systemic toxicity of adult mice. Portal vein administration produced the highest serum levels of hFIX and demonstrated proportionally higher levels of gene transfer to the liver with up to 4% of hepatocytes expressing hFIX. Vascular delivery of a lentiviral vector encoding GFP resulted in genetic modification of up to 12% of liver cells. Cell proliferation was not required for hepatocyte transduction with either vector. Serum hFIX levels reached 4% of normal levels following vascular LV-mediated hFIX gene transfer and remained stable for months following vector administration.
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