Threshold for Pre-existing Antibody Levels Limiting Transduction Efficiency of Systemic rAAV9 Gene Delivery: Relevance for Translation
Widespread anti-AAV antibodies (Abs) in humans pose a critical challenge for the translation of AAV gene therapies, limiting patient eligibility. In this study, non-human primates (NHPs) with pre-existing αAAV Abs were used to investigate the impact of αAAV9 Ab levels on the transduction efficiency...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-06-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050119300373 |
| _version_ | 1811270441010987008 |
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| author | Aaron S. Meadows Ricardo J. Pineda Laurie Goodchild Tierra A. Bobo Haiyan Fu |
| author_facet | Aaron S. Meadows Ricardo J. Pineda Laurie Goodchild Tierra A. Bobo Haiyan Fu |
| author_sort | Aaron S. Meadows |
| collection | DOAJ |
| description | Widespread anti-AAV antibodies (Abs) in humans pose a critical challenge for the translation of AAV gene therapies, limiting patient eligibility. In this study, non-human primates (NHPs) with pre-existing αAAV Abs were used to investigate the impact of αAAV9 Ab levels on the transduction efficiency of rAAV9 via systemic delivery. No significant differences were observed in vector genome (vg) biodistribution in animals with ≤1:400 total serum αAAV9-IgG compared to αAAV9-Ab-negative animals, following an intravenous (i.v.) rAAV9-hNAGLUop (codon-optimized human α-N-acetylglucosaminidase coding sequence cDNA) injection. Serum αAAV9-IgG at >1:400 resulted in a >200-fold decrease in vg in the liver, but had no significant effect on vg levels in brain and most of the peripheral tissues. Although tissue NAGLU activities declined significantly, they remained above endogenous levels. Notably, there were higher vg copies but lower NAGLU activity in the spleen in NHPs with >1:400 αAAV9 Abs than in those with ≤1:400 Abs. We demonstrate here the presence of a threshold of pre-existing αAAV9 Abs for diminishing the transduction of i.v.-delivered AAV vectors, supporting the expansion of patient eligibility for systemic rAAV treatments. Our data also indicate that high pre-existing αAAV9 Abs may promote phagocytosis and that phagocytized vectors are not processed for transgene expression, suggesting that effectively suppressing innate immunity may have positive impacts on transduction efficiency in individuals with high Ab titers. |
| first_indexed | 2024-04-12T22:01:53Z |
| format | Article |
| id | doaj.art-a72dbf99e1db4e7aa426fa65a2f5e803 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-04-12T22:01:53Z |
| publishDate | 2019-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-a72dbf99e1db4e7aa426fa65a2f5e8032022-12-22T03:15:05ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012019-06-0113453462Threshold for Pre-existing Antibody Levels Limiting Transduction Efficiency of Systemic rAAV9 Gene Delivery: Relevance for TranslationAaron S. Meadows0Ricardo J. Pineda1Laurie Goodchild2Tierra A. Bobo3Haiyan Fu4Center for Gene Therapy, Research Institute at Nationwide Children’s Hospital, Columbus, OH, USACenter for Gene Therapy, Research Institute at Nationwide Children’s Hospital, Columbus, OH, USAVivarium, Research Institute at Nationwide Children’s Hospital, Columbus, OH, USADepartment of Pediatrics, Division of Genetics and Metabolism, Gene Therapy Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USACenter for Gene Therapy, Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA; Department of Pediatrics, Division of Genetics and Metabolism, Gene Therapy Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Corresponding author: Haiyan Fu, Department of Pediatrics, Division of Genetics and Metabolism, Gene Therapy Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.Widespread anti-AAV antibodies (Abs) in humans pose a critical challenge for the translation of AAV gene therapies, limiting patient eligibility. In this study, non-human primates (NHPs) with pre-existing αAAV Abs were used to investigate the impact of αAAV9 Ab levels on the transduction efficiency of rAAV9 via systemic delivery. No significant differences were observed in vector genome (vg) biodistribution in animals with ≤1:400 total serum αAAV9-IgG compared to αAAV9-Ab-negative animals, following an intravenous (i.v.) rAAV9-hNAGLUop (codon-optimized human α-N-acetylglucosaminidase coding sequence cDNA) injection. Serum αAAV9-IgG at >1:400 resulted in a >200-fold decrease in vg in the liver, but had no significant effect on vg levels in brain and most of the peripheral tissues. Although tissue NAGLU activities declined significantly, they remained above endogenous levels. Notably, there were higher vg copies but lower NAGLU activity in the spleen in NHPs with >1:400 αAAV9 Abs than in those with ≤1:400 Abs. We demonstrate here the presence of a threshold of pre-existing αAAV9 Abs for diminishing the transduction of i.v.-delivered AAV vectors, supporting the expansion of patient eligibility for systemic rAAV treatments. Our data also indicate that high pre-existing αAAV9 Abs may promote phagocytosis and that phagocytized vectors are not processed for transgene expression, suggesting that effectively suppressing innate immunity may have positive impacts on transduction efficiency in individuals with high Ab titers.http://www.sciencedirect.com/science/article/pii/S2329050119300373 |
| spellingShingle | Aaron S. Meadows Ricardo J. Pineda Laurie Goodchild Tierra A. Bobo Haiyan Fu Threshold for Pre-existing Antibody Levels Limiting Transduction Efficiency of Systemic rAAV9 Gene Delivery: Relevance for Translation Molecular Therapy: Methods & Clinical Development |
| title | Threshold for Pre-existing Antibody Levels Limiting Transduction Efficiency of Systemic rAAV9 Gene Delivery: Relevance for Translation |
| title_full | Threshold for Pre-existing Antibody Levels Limiting Transduction Efficiency of Systemic rAAV9 Gene Delivery: Relevance for Translation |
| title_fullStr | Threshold for Pre-existing Antibody Levels Limiting Transduction Efficiency of Systemic rAAV9 Gene Delivery: Relevance for Translation |
| title_full_unstemmed | Threshold for Pre-existing Antibody Levels Limiting Transduction Efficiency of Systemic rAAV9 Gene Delivery: Relevance for Translation |
| title_short | Threshold for Pre-existing Antibody Levels Limiting Transduction Efficiency of Systemic rAAV9 Gene Delivery: Relevance for Translation |
| title_sort | threshold for pre existing antibody levels limiting transduction efficiency of systemic raav9 gene delivery relevance for translation |
| url | http://www.sciencedirect.com/science/article/pii/S2329050119300373 |
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