Dosing and Re-Administration of Lentiviral Vector for In Vivo Gene Therapy in Rhesus Monkeys and ADA-Deficient Mice
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 treat...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-03-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050119301299 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 Dosing and Re-Administration of Lentiviral Vector for In Vivo Gene Therapy in Rhesus Monkeys and ADA-Deficient Mice Molecular Therapy: Methods & Clinical Development |
| author_facet |
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 |
| author_sort |
Denise A. Carbonaro-Sarracino |
| title |
Dosing and Re-Administration of Lentiviral Vector for In Vivo Gene Therapy in Rhesus Monkeys and ADA-Deficient Mice |
| title_short |
Dosing and Re-Administration of Lentiviral Vector for In Vivo Gene Therapy in Rhesus Monkeys and ADA-Deficient Mice |
| title_full |
Dosing and Re-Administration of Lentiviral Vector for In Vivo Gene Therapy in Rhesus Monkeys and ADA-Deficient Mice |
| title_fullStr |
Dosing and Re-Administration of Lentiviral Vector for In Vivo Gene Therapy in Rhesus Monkeys and ADA-Deficient Mice |
| title_full_unstemmed |
Dosing and Re-Administration of Lentiviral Vector for In Vivo Gene Therapy in Rhesus Monkeys and ADA-Deficient Mice |
| title_sort |
dosing and re-administration of lentiviral vector for in vivo gene therapy in rhesus monkeys and ada-deficient mice |
| publisher |
Elsevier |
| series |
Molecular Therapy: Methods & Clinical Development |
| issn |
2329-0501 |
| publishDate |
2020-03-01 |
| description |
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 |
| url |
http://www.sciencedirect.com/science/article/pii/S2329050119301299 |
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doaj-95dac2eae6624eef9a74c31c79e92b592020-11-25T03:08:08ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012020-03-01167893Dosing and Re-Administration of Lentiviral Vector for In Vivo Gene Therapy in Rhesus Monkeys and ADA-Deficient MiceDenise A. Carbonaro-Sarracino0Alice F. Tarantal1C. Chang I. Lee2Michael L. Kaufman3Stephen Wandro4Xiangyang Jin5Michele Martinez6Danielle N. Clark7Krista Chun8Colin Koziol9Cinnamon L. Hardee10Xiaoyan Wang11Donald B. Kohn12Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USACenter 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, USACenter 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, USADepartment of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USADepartment of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USADepartment of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USACenter 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, USADepartment of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USADepartment of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USADepartment of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USADepartment of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USADepartment of General Internal Medicine and Health Services Research, University of California, Los Angeles, Los Angeles, CA 90095, USADepartment 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.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 administrationhttp://www.sciencedirect.com/science/article/pii/S2329050119301299 |