Production of human clotting Factor IX without toxicity in mice after vascular delivery of a lentiviral vector.
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.
Tsui
Lisa V
LV
Cell Genesys Inc., 342 Lakeside Drive, Foster City CA 94404, USA.
Kelly
Michael
M
Zayek
Nathalie
N
Rojas
Virginia
V
Ho
Ken
K
Ge
Ying
Y
Moskalenko
Marina
M
Mondesire
Jean
J
Davis
Jennifer
J
Roey
Melinda Van
MV
Dull
Tom
T
McArthur
James G
JG
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
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