Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response.
Nat Med
; 12(3): 342-7, 2006 Mar.
Article
em En
| MEDLINE
| ID: mdl-16474400
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução Genética
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Fator IX
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Terapia Genética
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Dependovirus
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Hemofilia A
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Fígado
Limite:
Adult
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Animals
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2006
Tipo de documento:
Article