title: Production of human clotting Factor IX without toxicity in mice after vascular delivery of a lentiviral vector.
abstract: 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.
authors.affiliation: Cell Genesys Inc., 342 Lakeside Drive, Foster City CA 94404, USA.
authors.forename: Lisa V
authors.initials: LV
authors.lastname: Tsui
authors.forename: Michael
authors.initials: M
authors.lastname: Kelly
authors.forename: Nathalie
authors.initials: N
authors.lastname: Zayek
authors.forename: Virginia
authors.initials: V
authors.lastname: Rojas
authors.forename: Ken
authors.initials: K
authors.lastname: Ho
authors.forename: Ying
authors.initials: Y
authors.lastname: Ge
authors.forename: Marina
authors.initials: M
authors.lastname: Moskalenko
authors.forename: Jean
authors.initials: J
authors.lastname: Mondesire
authors.forename: Jennifer
authors.initials: J
authors.lastname: Davis
authors.forename: Melinda Van
authors.initials: MV
authors.lastname: Roey
authors.forename: Tom
authors.initials: T
authors.lastname: Dull
authors.forename: James G
authors.initials: JG
authors.lastname: McArthur
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division; D005164:Factor IX / Q000096:biosynthesis* / Q000737:chemistry*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D022781:Hepatocytes / Q000378:metabolism; D007150:Immunohistochemistry; D007700:Kinetics; D016086:Lentivirus / Q000235:genetics*; D008164:Luminescent Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D019076:Transgenes / Q000235:genetics; D014759:Viral Envelope Proteins / Q000235:genetics
chemical_list: C028391:G protein, vesicular stomatitis virus; D008164:Luminescent Proteins; D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins; D049452:Green Fluorescent Proteins; D005164:Factor IX; D001973:Bromodeoxyuridine