In vivo treatment of hemophilia A and mucopolysaccharidosis type VII usingnonprimate lentiviral vectors

Gene therapy holds great promise for the treatment of a variety of inherite d diseases, including hemophilia A and mucopolysaccharidosis type VII (MPS VII). In both these disorders, subnormal levels of replacement protein have therapeutic effects. Thus we hypothesized that transduction of a small pro portion of cells by feline immunodeficiency virus (FIV)-based lentiviral ve ctors might provide sufficient levels of transgene expression for phenotypi c correction. We intravenously injected replication-deficient FIV-based vec tors encoding either human factor VIII or human beta -glucuronidase into fa ctor VIII-deficient or beta -glucuronidase-deficient mice, respectively. Th is route of delivery targeted multiple organs, with the liver as the primar y transduction site. In the hemophilia A mice, factor VIII expression persi sted for the duration of the experiments (approximately 5 months), and reci pient mice survived an otherwise lethal bleeding episode (tall-clipping). I n mucopolysaccharidosis type VII mice, substantial beta -glucuronidase acti vity was detected in several tissues and corresponded with marked reduction of lysosomal storage in liver and spleen. These findings indicate that gen e transfer with FIV-based lentiviral vectors can permanently introduce tran sgenes into a sufficient number of hepatocytes for long-term therapeutic ef fect and suggest potential clinical value of FIV-based lentiviral vectors f or treatment of hemophilia A and MPS VII.