Intravenous immunoglobulin prevents peripheral liver transduction of intrathecally delivered AAV vectors
Gene therapy using neurotropic adeno-associated virus vectors represents an emerging solution for genetic disorders affecting the central nervous system. The first approved central nervous system-targeting adeno-associated virus gene therapy, Zolgensma®, for treating spinal muscular atrophy is admin...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050122001425 |
| _version_ | 1811250653954048000 |
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| author | Makoto Horiuchi Christian J. Hinderer Jenny A. Greig Cecilia Dyer Elizabeth L. Buza Peter Bell Jessica A. Chichester Peter M. Hayashi Hanying Yan Tamara Goode James M. Wilson |
| author_facet | Makoto Horiuchi Christian J. Hinderer Jenny A. Greig Cecilia Dyer Elizabeth L. Buza Peter Bell Jessica A. Chichester Peter M. Hayashi Hanying Yan Tamara Goode James M. Wilson |
| author_sort | Makoto Horiuchi |
| collection | DOAJ |
| description | Gene therapy using neurotropic adeno-associated virus vectors represents an emerging solution for genetic disorders affecting the central nervous system. The first approved central nervous system-targeting adeno-associated virus gene therapy, Zolgensma®, for treating spinal muscular atrophy is administered intravenously at high doses that cause liver-associated adverse events in 20%–30% of patients. Intrathecal routes of vector administration, such as the intra-cisterna magna route, provide efficient gene transduction to central nervous system cells while reducing off-target liver transduction. However, significant levels of liver transduction often occur upon intra-cisterna magna vector delivery in preclinical studies. Using vectors expressing monoclonal antibody transgenes, we examined whether passive transfer of adeno-associated virus-neutralizing antibodies as intravenous immunoglobulin before intrathecal adeno-associated virus delivery improved the safety of viral gene therapy targeting the central nervous system in mice and nonhuman primates. We used intracerebroventricular and intra-cisterna magna routes for vector administration to mice and nonhuman primates, respectively, and evaluated transgene expression and vector genome distribution. Our data indicate that pretreatment with intravenous immunoglobulin significantly reduced gene transduction to the liver and other peripheral organs but not to the central nervous system in both species. With further refinement, this method may improve the safety of adeno-associated virus-based, central nervous system-targeting gene therapies in clinical settings. |
| first_indexed | 2024-04-12T16:07:53Z |
| format | Article |
| id | doaj.art-47d10615a3624fa0872c118998bf302a |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-04-12T16:07:53Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-47d10615a3624fa0872c118998bf302a2022-12-22T03:25:59ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012022-12-0127272280Intravenous immunoglobulin prevents peripheral liver transduction of intrathecally delivered AAV vectorsMakoto Horiuchi0Christian J. Hinderer1Jenny A. Greig2Cecilia Dyer3Elizabeth L. Buza4Peter Bell5Jessica A. Chichester6Peter M. Hayashi7Hanying Yan8Tamara Goode9James M. Wilson10Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAGene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAGene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAGene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAGene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAGene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAGene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAGene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAGene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAGene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAGene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author James M. Wilson, Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, 125 South 31st Street, Suite 1200, Philadelphia, PA 19104, USA.Gene therapy using neurotropic adeno-associated virus vectors represents an emerging solution for genetic disorders affecting the central nervous system. The first approved central nervous system-targeting adeno-associated virus gene therapy, Zolgensma®, for treating spinal muscular atrophy is administered intravenously at high doses that cause liver-associated adverse events in 20%–30% of patients. Intrathecal routes of vector administration, such as the intra-cisterna magna route, provide efficient gene transduction to central nervous system cells while reducing off-target liver transduction. However, significant levels of liver transduction often occur upon intra-cisterna magna vector delivery in preclinical studies. Using vectors expressing monoclonal antibody transgenes, we examined whether passive transfer of adeno-associated virus-neutralizing antibodies as intravenous immunoglobulin before intrathecal adeno-associated virus delivery improved the safety of viral gene therapy targeting the central nervous system in mice and nonhuman primates. We used intracerebroventricular and intra-cisterna magna routes for vector administration to mice and nonhuman primates, respectively, and evaluated transgene expression and vector genome distribution. Our data indicate that pretreatment with intravenous immunoglobulin significantly reduced gene transduction to the liver and other peripheral organs but not to the central nervous system in both species. With further refinement, this method may improve the safety of adeno-associated virus-based, central nervous system-targeting gene therapies in clinical settings.http://www.sciencedirect.com/science/article/pii/S2329050122001425AAVintrathecalintravenous immunoglobulinneutralizing antibodiescentral nervous system |
| spellingShingle | Makoto Horiuchi Christian J. Hinderer Jenny A. Greig Cecilia Dyer Elizabeth L. Buza Peter Bell Jessica A. Chichester Peter M. Hayashi Hanying Yan Tamara Goode James M. Wilson Intravenous immunoglobulin prevents peripheral liver transduction of intrathecally delivered AAV vectors Molecular Therapy: Methods & Clinical Development AAV intrathecal intravenous immunoglobulin neutralizing antibodies central nervous system |
| title | Intravenous immunoglobulin prevents peripheral liver transduction of intrathecally delivered AAV vectors |
| title_full | Intravenous immunoglobulin prevents peripheral liver transduction of intrathecally delivered AAV vectors |
| title_fullStr | Intravenous immunoglobulin prevents peripheral liver transduction of intrathecally delivered AAV vectors |
| title_full_unstemmed | Intravenous immunoglobulin prevents peripheral liver transduction of intrathecally delivered AAV vectors |
| title_short | Intravenous immunoglobulin prevents peripheral liver transduction of intrathecally delivered AAV vectors |
| title_sort | intravenous immunoglobulin prevents peripheral liver transduction of intrathecally delivered aav vectors |
| topic | AAV intrathecal intravenous immunoglobulin neutralizing antibodies central nervous system |
| url | http://www.sciencedirect.com/science/article/pii/S2329050122001425 |
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