title: In vivo hepatic gene therapy: complete albeit transient correction of factor IX deficiency in hemophilia B dogs.
abstract: Hemophilia B is a bleeding disorder caused by mutations in the factor IX gene. The disorder is X-linked recessive with a prevalence of about 1 in 30,000 Caucasian males. Factor IX is naturally synthesized in the liver and secreted into blood. Here we report the construction of recombinant adenoviral vectors containing the canine factor IX cDNA that are capable of transducing hepatocytes in mice at high efficiencies in vivo without partial hepatectomy. The recombinant viral vector was used to treat hemophilia B dogs by direct vector infusion into the portal vasculature of deficient animals. Plasma factor IX concentrations in the treated hemophilia B dogs increased from 0 to 300% of the level present in normal dogs, resulting in complete amelioration of the disease as demonstrated by normal blood coagulation and hemostatic measurements. Although plasma factor IX concentration started to decline after a few days, therapeutic levels of factor IX persisted for 1-2 months in the treated animals. The results validate the principle of in vivo hepatic gene delivery to reconstitute the genetic deficiency in a large animal model and suggest that gene therapy is achievable when long-acting vectors are developed.
authors.affiliation: Howard Hughes Medical Institute, Department of Cell Biology and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030.
authors.forename: M A
authors.initials: MA
authors.lastname: Kay
authors.forename: C N
authors.initials: CN
authors.lastname: Landen
authors.forename: S R
authors.initials: SR
authors.lastname: Rothenberg
authors.forename: L A
authors.initials: LA
authors.lastname: Taylor
authors.forename: F
authors.initials: F
authors.lastname: Leland
authors.forename: S
authors.initials: S
authors.lastname: Wiehle
authors.forename: B
authors.initials: B
authors.lastname: Fang
authors.forename: D
authors.initials: D
authors.lastname: Bellinger
authors.forename: M
authors.initials: M
authors.lastname: Finegold
authors.forename: A R
authors.initials: AR
authors.lastname: Thompson
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D004279:DNA, Viral; D004285:Dogs; D005164:Factor IX / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D002836:Hemophilia B / Q000235:genetics / Q000628:therapy*; D006498:Hepatectomy; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D014161:Transduction, Genetic; D014960:X Chromosome
chemical_list: D004279:DNA, Viral; D005164:Factor IX