Journal article
Immunosuppression reduces rAAV2.5T neutralizing antibodies that limit efficacy following repeat dosing to ferret lungs
Molecular therapy. Methods & clinical development, Vol.29, pp.70-80
06/08/2023
DOI: 10.1016/j.omtm.2023.02.015
PMCID: PMC10025970
PMID: 36950451
Abstract
The efficacy of redosing the recombinant adeno-associated virus (rAAV) vector rAAV2.5T to ferret lung is limited by AAV neutralizing antibody (NAb) responses. While immunosuppression strategies have allowed for systemic rAAV repeat dosing, their utility for rAAV lung-directed gene therapy is largely unexplored. To this end, we evaluated two immunosuppression (IS) strategies to improve repeat dosing of rAAV2.5T to ferret lungs: (1) a combination of three IS drugs (Tri-IS) with broad coverage against cellular and humoral responses (methylprednisolone [MP], azathioprine, and cyclosporine) and (2) MP alone, which is typically used in systemic rAAV applications. Repeat dosing utilized AAV2.5T-SP183-fCFTRΔR (recombinant ferret CFTR transgene), followed 28 days later by AAV2.5T-SP183-gLuc (for quantification of transgene expression). Both the Tri-IS and MP strategies significantly improved transgene expression following repeat dosing and reduced AAV2.5T NAb responses in the bronchioalveolar lavage fluid (BALF) and plasma, while AAV2.5T binding antibody subtypes and cellular immune responses by ELISpot were largely unchanged by IS. One exception was the reduction in plasma AAV2.5T binding immunoglobulin G (IgG) in both IS groups. Only the Tri-IS strategy significantly suppressed splenocyte expression of IFNA (interferon α [IFN-α]) and IL4. Our studies suggest that IS strategies may be useful in clinical application of rAAV targeting lung genetic diseases such as cystic fibrosis.
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John Engelhardt and colleagues developed an immunosuppressive strategy to mitigate neutralizing antibody responses to an AAV2.5T (adeno-associated viral vector) and improve transgene expression following repeat administration to the ferret lung for gene therapy of cystic fibrosis.
Details
- Title: Subtitle
- Immunosuppression reduces rAAV2.5T neutralizing antibodies that limit efficacy following repeat dosing to ferret lungs
- Creators
- Yinghua Tang - University of IowaShahab Fakhari - Department of Anatomy & Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USAEric D. Huntemann - Department of Anatomy & Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USAZehua Feng - University of IowaPeipei Wu - University of IowaWilliam Y. Feng - Department of Anatomy & Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USAJunying Lei - University of IowaFeng Yuan - University of IowaKatherine J. Excoffon - Spirovant Science, Inc., Philadelphia, PA 19104, USAKai Wang - Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA 52242, USAMaria P. Limberis - Spirovant Science, Inc., Philadelphia, PA 19104, USARoland Kolbeck - Spirovant Science, Inc., Philadelphia, PA 19104, USAZiying Yan - Department of Anatomy & Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USAJohn F. Engelhardt - Department of Anatomy & Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- Molecular therapy. Methods & clinical development, Vol.29, pp.70-80
- DOI
- 10.1016/j.omtm.2023.02.015
- PMID
- 36950451
- PMCID
- PMC10025970
- NLM abbreviation
- Mol Ther Methods Clin Dev
- ISSN
- 2329-0501
- eISSN
- 2329-0501
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 06/08/2023
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Biostatistics; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984380461502771
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