We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 x 10(12) vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of approximately 8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression.

Anatomical, histological, and histochemical studies were performed on normal and abnormal fat pads of the sole of cadaver feet. The fat pads were found to contain a significant nerve and blood supply separate from that to the surrounding musculature and skin. Pacinian corpuscles and free nerve endings within the fat were identified. Histological analysis indicated a meshwork of fibroelastic septae arranged in a closed-cell configuration. The mechanical consequences of this organization are discussed in the context of the weightbearing role of the fat pads of the feet. Alterations seen in dysvascular or senescent feet are consistent with the hypothesis that the septal anatomy of the fat pads is central to their cushioning function.

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