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Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector.

Abstract：

:Hemophilia B is a severe X-linked bleeding diathesis caused by the absence of functional blood coagulation factor IX, and is an excellent candidate for treatment of a genetic disease by gene therapy. Using an adeno-associated viral vector, we demonstrate sustained expression (>17 months) of factor IX in a large-animal model at levels that would have a therapeutic effect in humans (up to 70 ng/ml, adequate to achieve phenotypic correction, in an animal injected with 8.5x10(12) vector particles/kg). The five hemophilia B dogs treated showed stable, vector dose-dependent partial correction of the whole blood clotting time and, at higher doses, of the activated partial thromboplastin time. In contrast to other viral gene delivery systems, this minimally invasive procedure, consisting of a series of percutaneous intramuscular injections at a single timepoint, was not associated with local or systemic toxicity. Efficient gene transfer to muscle was shown by immunofluorescence staining and DNA analysis of biopsied tissue. Immune responses against factor IX were either absent or transient. These data provide strong support for the feasibility of the approach for therapy of human subjects.

journal_name

Nat Med

journal_title

Nature medicine

authors

Herzog RW,Yang EY,Couto LB,Hagstrom JN,Elwell D,Fields PA,Burton M,Bellinger DA,Read MS,Brinkhous KM,Podsakoff GM,Nichols TC,Kurtzman GJ,High KA

doi

10.1038/4743

subject

Has Abstract

pub_date

1999-01-01 00:00:00

pages

56-63

issue

1

eissn

1078-8956

issn

1546-170X

journal_volume

5

pub_type

杂志文章

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