title: In vivo treatment of hemophilia A and mucopolysaccharidosis type VII using nonprimate lentiviral vectors.
abstract: Gene therapy holds great promise for the treatment of a variety of inherited 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 proportion of cells by feline immunodeficiency virus (FIV)-based lentiviral vectors might provide sufficient levels of transgene expression for phenotypic correction. We intravenously injected replication-deficient FIV-based vectors encoding either human factor VIII or human beta-glucuronidase into factor VIII-deficient or beta-glucuronidase-deficient mice, respectively. This route of delivery targeted multiple organs, with the liver as the primary transduction site. In the hemophilia A mice, factor VIII expression persisted for the duration of the experiments (approximately 5 months), and recipient mice survived an otherwise lethal bleeding episode (tail-clipping). In mucopolysaccharidosis type VII mice, substantial beta-glucuronidase activity was detected in several tissues and corresponded with marked reduction of lysosomal storage in liver and spleen. These findings indicate that gene transfer with FIV-based lentiviral vectors can permanently introduce transgenes into a sufficient number of hepatocytes for long-term therapeutic effect and suggest potential clinical value of FIV-based lentiviral vectors for treatment of hemophilia A and MPS VII.
authors.affiliation: Program in Gene Therapy, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Stein
authors.forename: Y
authors.initials: Y
authors.lastname: Kang
authors.forename: S L
authors.initials: SL
authors.lastname: Sauter
authors.forename: K
authors.initials: K
authors.lastname: Townsend
authors.forename: P
authors.initials: P
authors.lastname: Staber
authors.forename: T A
authors.initials: TA
authors.lastname: Derksen
authors.forename: I
authors.initials: I
authors.lastname: Martins
authors.forename: J
authors.initials: J
authors.lastname: Qian
authors.forename: B L
authors.initials: BL
authors.lastname: Davidson
authors.forename: P B
authors.initials: PB
authors.lastname: McCray
mesh_terms: D000818:Animals; D017931:DNA Primers / Q000737:chemistry; D003673:Defective Viruses; D004195:Disease Models, Animal; D005169:Factor VIII / Q000235:genetics* / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D005966:Glucuronidase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D006467:Hemophilia A / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016089:Immunodeficiency Virus, Feline / Q000235:genetics*; D007275:Injections, Intravenous; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016538:Mucopolysaccharidosis VII / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D005169:Factor VIII; D005966:Glucuronidase