Clinical results following hepatic artery infusion of AAV2-F.IX. (A) Time course of F.IX levels and of transaminases in first subject to receive high-dose AAV2-F.IX (2 × 10¹² vg/kg) in hemophilia B trial. An F.IX level (red) of ∼10% persists for 4 weeks and then slowly declines, concomitant with a self-limited rise in liver transaminases, which peaked at levels close to 10-fold over the baseline and then gradually fell, in tandem with a falling F.IX level, so that all laboratory parameters had returned to the patient’s baseline by ∼12 weeks after vector infusion (ALT, blue; AST, green). The patient remained asymptomatic throughout these events and, when tested subsequently, responded normally to infused recombinant F.IX. (B) A subsequent subject received a fivefold lower dose, 4 × 10¹¹ vg/kg. F.IX levels (red) did not rise above 1%, but liver enzymes (ALT, blue; AST, green) rose and fell in a time course similar to that seen in the previous subject. Note difference in scales of liver enzymes. ALT, alanine aminotransferase; AST, aspartate aminotransferase. Reprinted from Manno et al.¹⁵