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TY - JOUR AU - Manno, Catherine S AU - Pierce, Glenn F AU - Arruda, Valder R AU - Glader, Bertil AU - Ragni, Margaret AU - Rasko, John J E AU - Ozelo, Margareth C AU - Hoots, Keith AU - Blatt, Philip AU - Konkle, Barbara AU - Dake, Michael AU - Kaye, Robin AU - Razavi, Mahmood AU - Zajko, Albert AU - Zehnder, James AU - Rustagi , Pradip AU - Nakai, Hiroyuki AU - Chew, Amy AU - Leonard, Debra AU - Wright, J Fraser AU - Lessard, Ruth R AU - Sommer, Jürg M AU - Tigges, Michael AU - Sabatino, Denise AU - Luk, Alvin AU - Jiang, Haiyan AU - Mingozzi, Federico AU - Couto, Linda AU - Ertl, Hildegund C AU - High, Katherine A AU - Kay, Mark A PY - 2006 DA - 2006/03/01 TI - Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response JO - Nature Medicine SP - 342 EP - 347 VL - 12 IS - 3 AB - 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 B1. 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*. SN - 1546-170X UR - https://doi.org/10.1038/nm1358 DO - 10.1038/nm1358 ID - Manno2006 ER -