In vivo efficacy of AAV-mediated gene transfer of cFVIIa in hemophilia A and B dogs. (A) AAV8 vector used for infusion in hemophilia mice and dogs. Inverted terminal repeats (ITRs) flank the expression cassette composed of an hAAT/apoE promoter/enhancer, a synthetic intron, the cFVIIa cDNA (with 5′ UTR and absence of the HPC4 tag) and a polyadenylation signal (pA) from bovine growth hormone. (B) PT and aPTT in HA mice (n = 6) after tail vein administration of AAV8-cFVIIa. A shaded box represents the range of values for aPTT in normal (N) mice, determined from at least 4 mice. (C) WBCT after portal vein AAV8-cFVIIa vector administration () in HA and HB dogs. A shaded box represents the range of values for normal dogs. A vertical dotted line represents day 0. Prophylactic plasma treatment was administered on days 2 to 4 (HA-1-J55, HA-2-J57), 2 to 5 (HA-3-E66), and 1 to 5 as well as for 2 days after nonspontaneous bleeding episodes in the HB dog (occurring on days 11, 159, and 228 after AAV administration). (D) PT after portal vein AAV8-cFVIIa vector administration () in HA and HB dogs. A shaded box represents the range of values for normal dogs. A vertical dotted line represents day 0. (E) cFVIIa expression after portal vein AAV8-cFVIIa vector administration () in HA and HB dogs. A shaded box represents the range of values for normal, HA, and HB dogs. (F) Reaction time (time to initial fibrin formation) in thromboelastography analysis of whole blood in the treated HA dogs after AAV8-cFVIIa vector infusion (). A shaded box represents the range of values for normal dogs.