Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response

CS Manno, GF Pierce, VR Arruda, B Glader, M Ragni… - Nature medicine, 2006 - nature.com
CS Manno, GF Pierce, VR Arruda, B Glader, M Ragni, JJE Rasko, MC Ozelo, K Hoots…
Nature medicine, 2006nature.com
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× 1012 vg/kg was …
Abstract
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 × 1012 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 ∼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*.
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