Severe hemophilia B patients maintain 5%. The clinical severity of the disease is inversely proportional to FIX levels in the plasma. Hemophilia B is an X-linked disorder caused by the deficiency of factor IX (FIX) activity. These results demonstrate that persistent secretion of the FIX transgene protein, necessary for successful gene therapy of hemophilia B, can be achieved using the parvovirus-based rAAV vector Analysis of both high and low molecular weight DNA identified both replicative episomal and integrated AAV species. Vector DNA and mRNA transcripts were detected only at the injected skeletal muscle tissue. Neutralizing antibodies directed against AAV-2 capsid were pronounced and persistent. Inhibitors to cFIX protein were not detected in either animal by Bethesda assay. Both dogs still required plasma infusion for spontaneous and traumatic bleeding events. Hemostatic correction (WBCT and APTT) paralleled plasma FIX antigen levels. Circulating cFIX protein levels were maintained for 1 year at levels of 1–2% of normal. To test the therapeutic efficacy of rAAV in hemophilic dogs, rAAV type 2 (rAAV2) carrying canine FIX (cFIX) cDNA was injected into the skeletal muscle of two dogs at doses of 10 12–13particles. We previously demonstrated that direct intramuscular injection of recombinant adeno-associated virus (rAAV) carrying the human FIX (hFIX) cDNA can safely be administered to hemophilic B canines and express human factor IX protein however, the functional activity of the hFIX protein could not be assessed due to anti-human FIX antibody (inhibitor) formation.

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