IN-VIVO HEPATIC GENE-THERAPY - COMPLETE ALBEIT TRANSIENT CORRECTION OF FACTOR-IX DEFICIENCY IN HEMOPHILIA-B DOGS

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 th e liver and secreted into blood. Here we report the construction of re combinant adenoviral vectors containing the canine factor IX cDNA that are capable of transducing hepatocytes in mice at high efficiencies i n vivo without partial hepatectomy. The recombinant viral vector was u sed to treat hemophilia B dogs by direct vector infusion into the port al vasculature of deficient animal. Plasma factor IX concentrations in the treated hemophilia B dogs increased from 0 to 300% of the level p resent in normal dogs, resulting in complete amelioration of the disea se as demonstrated by normal blood coagulation and hemostatic measurem ents. 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 larg e animal model and suggest that gene therapy is achievable when long-a cting vectors are developed.