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Type: Artigo de periódico
Title: Successful transduction of liver in hemophilia by AAV-factor IX and limitations imposed by the host immune response
Author: Manno, CS
Arruda, VR
Pierce, GF
Glader, B
Ragni, M
Rasko, J
Ozelo, MC
Hoots, K
Blatt, P
Konkle, B
Dake, M
Kaye, R
Razavi, M
Zajko, A
Zehnder, J
Nakai, H
Chew, A
Leonard, D
Wright, JF
Lessard, RR
Sommer, JM
Tigges, M
Sabatino, D
Luk, A
Jiang, HY
Mingozzi, F
Couto, L
Ertl, HC
High, KA
Kay, MA
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-1. 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 similar to 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.
Country: EUA
Editor: Nature Publishing Group
Citation: Nature Medicine. Nature Publishing Group, v. 12, n. 3, n. 342, n. 347, 2006.
Rights: fechado
Identifier DOI: 10.1038/nm1358
Date Issue: 2006
Appears in Collections:Unicamp - Artigos e Outros Documentos

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