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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.

journal_name

Nat Med

journal_title

Nature medicine

authors

Manno CS,Pierce GF,Arruda VR,Glader B,Ragni M,Rasko JJ,Ozelo MC,Hoots K,Blatt P,Konkle B,Dake M,Kaye R,Razavi M,Zajko A,Zehnder J,Rustagi PK,Nakai H,Chew A,Leonard D,Wright JF,Lessard RR,Sommer JM,Tigges M,S

doi

10.1038/nm1358

keywords:

subject

Has Abstract

pub_date

2006-03-01 00:00:00

pages

342-7

issue

3

eissn

1078-8956

issn

1546-170X

pii

nm1358

journal_volume

12

pub_type

杂志文章

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