Journal article
Persistent expression of factor VIII in vivo following nonprimate lentiviral gene transfer
Blood, Vol.106(5), pp.1552-1558
09/01/2005
DOI: 10.1182/blood-2004-11-4358
PMCID: PMC1895217
PMID: 15886327
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.
Details
- Title: Subtitle
- Persistent expression of factor VIII in vivo following nonprimate lentiviral gene transfer
- Creators
- Yubin Kang - 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 CityLitao Xie - 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 CityDiane Thi Tran - 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 CityColleen S Stein - 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 CityMelissa Hickey - 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 CityBeverly L Davidson - 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 CityPaul B McCray - 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
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.106(5), pp.1552-1558
- Publisher
- The American Society of Hematology
- DOI
- 10.1182/blood-2004-11-4358
- PMID
- 15886327
- PMCID
- PMC1895217
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Language
- English
- Date published
- 09/01/2005
- Academic Unit
- Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Internal Medicine
- Record Identifier
- 9984093221602771
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