title: Effects of vector backbone and pseudotype on lentiviral vector-mediated gene transfer: studies in infant ADA-deficient mice and rhesus monkeys.
abstract: Systemic delivery of a lentiviral vector carrying a therapeutic gene represents a new treatment for monogenic disease. Previously, we have shown that transfer of the adenosine deaminase (ADA) cDNA in vivo rescues the lethal phenotype and reconstitutes immune function in ADA-deficient mice. In order to translate this approach to ADA-deficient severe combined immune deficiency patients, neonatal ADA-deficient mice and newborn rhesus monkeys were treated with species-matched and mismatched vectors and pseudotypes. We compared gene delivery by the HIV-1-based vector to murine γ-retroviral vectors pseudotyped with vesicular stomatitis virus-glycoprotein or murine retroviral envelopes in ADA-deficient mice. The vesicular stomatitis virus-glycoprotein pseudotyped lentiviral vectors had the highest titer and resulted in the highest vector copy number in multiple tissues, particularly liver and lung. In monkeys, HIV-1 or simian immunodeficiency virus vectors resulted in similar biodistribution in most tissues including bone marrow, spleen, liver, and lung. Simian immunodeficiency virus pseudotyped with the gibbon ape leukemia virus envelope produced 10- to 30-fold lower titers than the vesicular stomatitis virus-glycoprotein pseudotype, but had a similar tissue biodistribution and similar copy number in blood cells. The relative copy numbers achieved in mice and monkeys were similar when adjusted to the administered dose per kg. These results suggest that this approach can be scaled-up to clinical levels for treatment of ADA-deficient severe combined immune deficiency subjects with suboptimal hematopoietic stem cell transplantation options.
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Carbonaro Sarracino
authors.affiliation: 1] Center for Fetal Monkey Gene Transfer for Heart, Lung, and Blood Diseases, University of California, Davis, California USA [2] Departments of Pediatrics and Cell Biology and Human Anatomy, University of California, Davis, CA, USA.
authors.forename: Alice F
authors.initials: AF
authors.lastname: Tarantal
authors.affiliation: Center for Fetal Monkey Gene Transfer for Heart, Lung, and Blood Diseases, University of California, Davis, California USA.
authors.forename: C Chang I
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Center for Fetal Monkey Gene Transfer for Heart, Lung, and Blood Diseases, University of California, Davis, California USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Martinez
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA.
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of General Internal Medicine and Health Services Research, University of California, Los Angeles California, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA.
authors.forename: Cinnamon L
authors.initials: CL
authors.lastname: Hardee
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA.
authors.forename: Sabine
authors.initials: S
authors.lastname: Geiger
authors.affiliation: 1] Division of Research Immunology/BMT, Children's Hospital Los Angeles, Los Angeles, California, USA [2] Current address: Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, USA.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Kahl
authors.affiliation: 1] Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA [2] Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Donald B
authors.initials: DB
authors.lastname: Kohn
mesh_terms: D000243:Adenosine Deaminase / Q000172:deficiency / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics* / Q000493:pharmacokinetics; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D008253:Macaca mulatta; D051379:Mice; D018345:Mice, Knockout; D012190:Retroviridae / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000628:therapy; D014018:Tissue Distribution; D014161:Transduction, Genetic; D019076:Transgenes
chemical_list: D000243:Adenosine Deaminase