Persistent expression of factor VIII in vivo following nonprimate lentiviral gene transfer
Journal Article
Abstract Hemophilia A is a clinically important coagulation disorder caused by the lack or abnormality of plasma coagulation factor VIII (FVIII). Gene transfer of the FVIII cDNA to hepatocytes using lentiviral vectors is a potential therapeutic approach. We investigated the efficacy of feline immunodeficiency virus (FIV)–based vectors in targeting hepatocytes and correcting FVIII deficiency in a hemophilia A mouse model. Several viral envelope glycoproteins were screened for efficient FIV vector pseudotyping and hepatocyte transduction. The GP64 glycoprotein from baculovirus Autographa californica multinuclear polyhedrosis virus pseudo-typed FIV efficiently and showed excellent hepatocyte tropism. The GP64-pseudotyped vector was stable in the presence of human or mouse complement. Inclusion of a hybrid liver-specific promoter (murine albumin enhancer/human α1-antitrypsin promoter) further enhanced transgene expression in hepatocytes. We generated a GP64-pseudotyped FIV vector encoding the B domain–deleted human FVIII coding region driven by the liver-specific promoter, with 2 beneficial point mutations in the A1 domain. Intravenous vector administration conferred sustained FVIII expression in hemophilia A mice for several months without the generation of anti–human FVIII antibodies and resulted in partial phenotypic correction. These findings demonstrate the utility of GP64-pseudotyped FIV lentiviral vectors for targeting hepatocytes to correct disorders associated with deficiencies of secreted proteins.
Full Text
Duke Authors
Cited Authors
- Kang, Y; Xie, L; Tran, DT; Stein, CS; Hickey, M; Davidson, BL; McCray, PB
Published Date
- September 1, 2005
Published In
Volume / Issue
- 106 / 5
Start / End Page
- 1552 - 1558
Published By
Electronic International Standard Serial Number (EISSN)
- 1528-0020
International Standard Serial Number (ISSN)
- 0006-4971
Digital Object Identifier (DOI)
- 10.1182/blood-2004-11-4358
Language
- en