Timing of Intensive Immunosuppression Impacts Risk of Transgene Antibodies after AAV Gene Therapy in Nonhuman Primates
Adeno-associated virus (AAV) vector gene therapy is a promising treatment for a variety of genetic diseases, including hemophilia. Systemic administration of AAV vectors is associated with a cytotoxic immune response triggered against AAV capsid proteins, which if untreated can result in loss of tra...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-06-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050120300887 |
| _version_ | 1828529781193310208 |
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| author | Benjamin J. Samelson-Jones Jonathan D. Finn Patricia Favaro J. Fraser Wright Valder R. Arruda |
| author_facet | Benjamin J. Samelson-Jones Jonathan D. Finn Patricia Favaro J. Fraser Wright Valder R. Arruda |
| author_sort | Benjamin J. Samelson-Jones |
| collection | DOAJ |
| description | Adeno-associated virus (AAV) vector gene therapy is a promising treatment for a variety of genetic diseases, including hemophilia. Systemic administration of AAV vectors is associated with a cytotoxic immune response triggered against AAV capsid proteins, which if untreated can result in loss of transgene expression. Immunosuppression (IS) with corticosteroids has limited transgene loss in some AAV gene therapy clinical trials, but was insufficient to prevent loss in other studies. We used a nonhuman primate model to evaluate intensive T cell-directed IS combined with AAV-mediated transfer of the human factor IX (FIX) gene. Early administration of rabbit anti-thymocyte globulin (ATG) concomitant with AAV administration resulted in the development of anti-FIX antibodies, whereas delayed ATG by 5 weeks administration did not. The anti-FIX immune response was associated with increases in inflammatory cytokines, as well as a skewed Th17/regulatory T cell (Treg) ratio. We conclude that the timing of T cell-directed IS is critical in determining transgene-product immunogenicity or tolerance. These data have implications for systemically administered AAV gene therapy being evaluated for hemophilia A and B, as well as other genetic diseases. |
| first_indexed | 2024-12-11T22:12:50Z |
| format | Article |
| id | doaj.art-9227e0fd576d42b5933de659d1866102 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-12-11T22:12:50Z |
| publishDate | 2020-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-9227e0fd576d42b5933de659d18661022022-12-22T00:48:42ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012020-06-011711291138Timing of Intensive Immunosuppression Impacts Risk of Transgene Antibodies after AAV Gene Therapy in Nonhuman PrimatesBenjamin J. Samelson-Jones0Jonathan D. Finn1Patricia Favaro2J. Fraser Wright3Valder R. Arruda4The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Philadelphia, PA 19104, USAThe Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USAThe Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USAThe Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Philadelphia, PA 19104, USAThe Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Philadelphia, PA 19104, USA; Corresponding author: Valder R. Arruda, MD, PhD, The Children’s Hospital of Philadelphia, 3501 Civic Center Boulevard, 5056 Colket Translational Research Center, Philadelphia, PA 19104, USA.Adeno-associated virus (AAV) vector gene therapy is a promising treatment for a variety of genetic diseases, including hemophilia. Systemic administration of AAV vectors is associated with a cytotoxic immune response triggered against AAV capsid proteins, which if untreated can result in loss of transgene expression. Immunosuppression (IS) with corticosteroids has limited transgene loss in some AAV gene therapy clinical trials, but was insufficient to prevent loss in other studies. We used a nonhuman primate model to evaluate intensive T cell-directed IS combined with AAV-mediated transfer of the human factor IX (FIX) gene. Early administration of rabbit anti-thymocyte globulin (ATG) concomitant with AAV administration resulted in the development of anti-FIX antibodies, whereas delayed ATG by 5 weeks administration did not. The anti-FIX immune response was associated with increases in inflammatory cytokines, as well as a skewed Th17/regulatory T cell (Treg) ratio. We conclude that the timing of T cell-directed IS is critical in determining transgene-product immunogenicity or tolerance. These data have implications for systemically administered AAV gene therapy being evaluated for hemophilia A and B, as well as other genetic diseases.http://www.sciencedirect.com/science/article/pii/S2329050120300887AAVgene therapygene transferimmunogenecitynonhuman primatestransgene immunogenecity |
| spellingShingle | Benjamin J. Samelson-Jones Jonathan D. Finn Patricia Favaro J. Fraser Wright Valder R. Arruda Timing of Intensive Immunosuppression Impacts Risk of Transgene Antibodies after AAV Gene Therapy in Nonhuman Primates Molecular Therapy: Methods & Clinical Development AAV gene therapy gene transfer immunogenecity nonhuman primates transgene immunogenecity |
| title | Timing of Intensive Immunosuppression Impacts Risk of Transgene Antibodies after AAV Gene Therapy in Nonhuman Primates |
| title_full | Timing of Intensive Immunosuppression Impacts Risk of Transgene Antibodies after AAV Gene Therapy in Nonhuman Primates |
| title_fullStr | Timing of Intensive Immunosuppression Impacts Risk of Transgene Antibodies after AAV Gene Therapy in Nonhuman Primates |
| title_full_unstemmed | Timing of Intensive Immunosuppression Impacts Risk of Transgene Antibodies after AAV Gene Therapy in Nonhuman Primates |
| title_short | Timing of Intensive Immunosuppression Impacts Risk of Transgene Antibodies after AAV Gene Therapy in Nonhuman Primates |
| title_sort | timing of intensive immunosuppression impacts risk of transgene antibodies after aav gene therapy in nonhuman primates |
| topic | AAV gene therapy gene transfer immunogenecity nonhuman primates transgene immunogenecity |
| url | http://www.sciencedirect.com/science/article/pii/S2329050120300887 |
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