Therapeutic levels of human factor VIII and IX using HIV-1-based lentiviral vectors in mouse liver.
Lentiviral vectors have the potential to play an important role in hemophilia gene therapy. The present study used human immunodeficiency virus (HIV)-based lentiviral vectors containing an EF1alpha enhancer/promoter driving human factors VIII (hFVIII) or IX (hFIX) complementary DNA expression for portal vein injection into C57Bl/6 mice. Increasing doses of hFIX-expressing lentivirus resulted in a dose-dependent, sustained increase in serum hFIX levels up to approximately 50-60 ng/mL. Partial hepatectomy resulted in a 4- to 6-fold increase (P < 0.005) in serum hFIX of up to 350 ng/mL compared with the nonhepatectomized counterparts. The expression of plasma hFVIII reached 30 ng/mL (15% of normal) but was transient as the plasma levels fell concomitant with the formation of anti-hFVIII antibodies. However, hFVIII levels were persistent in immunodeficient C57Bl/6 scid mice, suggesting humoral immunity-limited gene expression in immunocompetent mice. This study demonstrates that lentiviral vectors can produce therapeutic levels of coagulation factors in vivo, which can be enhanced with hepatocellular proliferation.
Park
F
F
Program in Human Gene Therapy, Departments of Pediatrics and Genetics, Stanford University, CA 94305, USA.
Ohashi
K
K
Kay
M A
MA
D000818:Animals; D005164:Factor IX / Q000096:biosynthesis / Q000235:genetics*; D005169:Factor VIII / Q000096:biosynthesis / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D008099:Liver; D051379:Mice; D011401:Promoter Regions, Genetic
D005169:Factor VIII; D005164:Factor IX