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Blood, 1 September 2005, Vol. 106, No. 5, pp. 1552-1558.
Prepublished online as a Blood First Edition Paper on May 10, 2005; DOI 10.1182/blood-2004-11-4358.
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GENE THERAPY
Persistent expression of factor VIII in vivo following nonprimate lentiviral gene transfer
Yubin Kang,
Litao Xie,
Diane Thi Tran,
Colleen S. Stein,
Melissa Hickey,
Beverly L. Davidson, and
Paul B. McCray, Jr
From the Program in Gene Therapy, Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City; Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City; Department of Neurology, University of Iowa Carver College of Medicine, Iowa City; and Department of Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City.
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  1-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.
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