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

Catherine S. Manno, Valder R. Arruda, Glenn F. Pierce, Bertil Glader, Margaret Ragni, John Rasko, Margareth C. Ozelo, Keith Hoots, Philip Blatt, Barbara Konkle, Michael Dake, Robin Kaye, Mahmood Razavi, Albert Zajko, James Zehnder, Hiroyuki Nakai, Amy Chew, Debra Leonard, J. Fraser Wright, Ruth R. LessardJürg M. Sommer, Michael Tigges, Denise Sabatino, Alvin Luk, Haiyan Jiang, Federico Mingozzi, Linda Couto, Hildegund C. Ertl, Katherine A. High, Mark A. Kay

Research output: Contribution to journalArticlepeer-review

1733 Scopus citations


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 × 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 ∼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.

Original languageEnglish (US)
Pages (from-to)342-347
Number of pages6
JournalNature medicine
Issue number3
StatePublished - Mar 2006
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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