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

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 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.

• Authors: Catherine S Manno, Glenn F Pierce, Valder R Arruda, Bertil Glader, Margaret Ragni, John J Rasko, John Rasko, Margareth C Ozelo, Keith Hoots, Philip Blatt, Barbara Konkle, Michael Dake, Robin Kaye, Mahmood Razavi, Albert Zajko, James Zehnder, Pradip K Rustagi, Hiroyuki Nakai, Amy Chew, Debra Leonard, J Fraser Wright, Ruth R Lessard, Jürg M Sommer, Michael Tigges, Denise Sabatino, Alvin Luk, Haiyan Jiang, Federico Mingozzi, Linda Couto, Hildegund C Ertl, Katherine A High, Mark A Kay
• Journal: Nature medicine (Nat Med) Vol. 12 Issue 3 Pg. 342-7 (Mar 2006) ISSN: 1078-8956 [Print] United States
• PMID: 16474400 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interferon-gamma
• Factor IX

Topics

• Adult
• Amino Acid Sequence
• Animals
• Dependovirus (genetics)
• Dogs
• Dose-Response Relationship, Drug
• Exons (genetics)
• Factor IX (genetics, immunology, metabolism, therapeutic use)
• Genetic Therapy
• Genetic Vectors (administration & dosage, genetics)
• Hemophilia A (genetics, immunology)
• Humans
• Interferon-gamma (metabolism)
• Introns (genetics)
• Liver (immunology, metabolism)
• Male
• Mice
• Middle Aged
• Molecular Sequence Data
• Monocytes (metabolism)
• Transduction, Genetic