Dosing and Re-Administration of Lentiviral Vector for In Vivo Gene Therapy in Rhesus Monkeys and ADA-Deficient Mice

Denise A. Carbonaro-Sarracino; Alice F. Tarantal; C. Chang I. Lee; Michael L. Kaufman; Stephen Wandro; Xiangyang Jin; Michele Martinez; Danielle N. Clark; Krista Chun; Colin Koziol; Cinnamon L. Hardee; Xiaoyan Wang; Donald B. Kohn

Molecular Therapy: Methods & Clinical Development (Mar 2020)

Dosing and Re-Administration of Lentiviral Vector for In Vivo Gene Therapy in Rhesus Monkeys and ADA-Deficient Mice

Denise A. Carbonaro-Sarracino,
Alice F. Tarantal,
C. Chang I. Lee,
Michael L. Kaufman,
Stephen Wandro,
Xiangyang Jin,
Michele Martinez,
Danielle N. Clark,
Krista Chun,
Colin Koziol,
Cinnamon L. Hardee,
Xiaoyan Wang,
Donald B. Kohn

Affiliations

Denise A. Carbonaro-Sarracino: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
Alice F. Tarantal: Center for Fetal Monkey Gene Transfer for Heart, Lung, and Blood Diseases, University of California, Davis, Davis, CA 95616, USA; Departments of Pediatrics and Cell Biology and Human Anatomy, School of Medicine, and California National Primate Research Center, University of California, Davis, Davis, CA 95616, USA
C. Chang I. Lee: Center for Fetal Monkey Gene Transfer for Heart, Lung, and Blood Diseases, University of California, Davis, Davis, CA 95616, USA; Departments of Pediatrics and Cell Biology and Human Anatomy, School of Medicine, and California National Primate Research Center, University of California, Davis, Davis, CA 95616, USA
Michael L. Kaufman: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
Stephen Wandro: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
Xiangyang Jin: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
Michele Martinez: Center for Fetal Monkey Gene Transfer for Heart, Lung, and Blood Diseases, University of California, Davis, Davis, CA 95616, USA; Departments of Pediatrics and Cell Biology and Human Anatomy, School of Medicine, and California National Primate Research Center, University of California, Davis, Davis, CA 95616, USA
Danielle N. Clark: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
Krista Chun: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
Colin Koziol: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
Cinnamon L. Hardee: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
Xiaoyan Wang: Department of General Internal Medicine and Health Services Research, University of California, Los Angeles, Los Angeles, CA 90095, USA
Donald B. Kohn: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; The Eli & Edythe Broad Center for Stem Cells and Regenerative Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Corresponding author: Donald B. Kohn, Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Journal volume & issue: Vol. 16
pp. 78 – 93

Abstract

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Adenosine deaminase (ADA)-deficient mice and healthy rhesus monkeys were studied to determine the impact of age at treatment, vector dosage, dosing schedule, repeat administration, biodistribution, and immunogenicity after systemic delivery of lentiviral vectors (LVs). In Ada−/− mice, neonatal treatment resulted in broad vector marking across all tissues analyzed, whereas adult treatment resulted in marking restricted to the liver, spleen, and bone marrow. Intravenous administration to infant rhesus monkeys also resulted in dose-dependent marking in the liver, spleen, and bone marrow. Using an ELISA to monitor anti-vector antibody development, Ada−/− neonatal mice did not produce an antibody response, whereas Ada−/− adult mice produced a strong antibody response to vector administration. In mice and monkeys with repeat administration of LV, a strong anti-vector antibody response was shown in response to the second LV administration, which resulted in LV inactivation. Three separate doses administered to immune competent mice resulted in acute toxicity. Pegylation of the vesicular stomatitis virus G protein (VSV-G)-enveloped LVs showed a less robust anti-vector response but did not prevent the inactivation of the second LV administration. These studies identify important factors to consider related to age and timing of administration when implementing systemic delivery of LVs as a potential therapeutic agent. Keywords: lentiviral vector, gene therapy, rhesus monkeys, in vivo, immune response, ADA-deficiency, ERT, repeat administration

Published in Molecular Therapy: Methods & Clinical Development

ISSN: 2329-0501 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Biology (General): Genetics; Science: Biology (General): Cytology
Website: http://www.cell.com/molecular-therapy-family/methods/latest-content

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