601. Persistent Expression of Factor VIII In Vivo Following FIV Lentiviral Gene Transfer

Yubin Kang; Litao Xie; Diane Thi Tran; Colleen S Stein; Melissa Hickey; Beverly L Davidson; Paul B Mccray

doi:10.1016/j.ymthe.2005.07.141

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601. Persistent Expression of Factor VIII In Vivo Following FIV Lentiviral Gene Transfer

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601. Persistent Expression of Factor VIII In Vivo Following FIV Lentiviral Gene Transfer

Yubin Kang, Litao Xie, Diane Thi Tran, Colleen S Stein, Melissa Hickey, Beverly L Davidson and Paul B Mccray

Molecular therapy, Vol.11(S1), pp.S232-S232

05/01/2005

DOI: 10.1016/j.ymthe.2005.07.141

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Abstract

Hemophilia A is a common X-linked 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 pseudotyped FIV efficiently and showed excellent hepatocyte tropism. The GP64 pseudotyped FIV 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 hepatoctyes. We generated a GP64-pseudotyped FIV vector encoding the B domain-deleted human FVIII coding region driven by the liver-specific promoter, with two 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.

Details

Title: Subtitle: 601. Persistent Expression of Factor VIII In Vivo Following FIV Lentiviral Gene Transfer
Creators: Yubin Kang
Litao Xie
Diane Thi Tran
Colleen S Stein
Melissa Hickey
Beverly L Davidson
Paul B Mccray
Resource Type: Abstract
Publication Details: Molecular therapy, Vol.11(S1), pp.S232-S232
Publisher: Elsevier Limited
DOI: 10.1016/j.ymthe.2005.07.141
ISSN: 1525-0016
eISSN: 1525-0024
Language: English
Date published: 05/01/2005
Academic Unit: Microbiology and Immunology; Internal Medicine; Stead Family Department of Pediatrics; Pulmonary Medicine
Record Identifier: 9984297621602771

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