Reduced retinal transduction and enhanced transgene-directed immunogenicity with intravitreal delivery of rAAV following posterior vitrectomy in dogs
Open accessAbstract
Adeno-associated virus (AAV) vector-based gene therapy is a promising treatment strategy for delivery of neurotrophic transgenes to retinal ganglion cells (RGCs) in glaucoma patients. Retinal distribution of transgene expression following intravitreal injection (IVT) of AAV is variable in animal models and the vitreous humor may represent a barrier to initial vector penetration. The primary goal of our study was to investigate the effect of prior core vitrectomy with posterior hyaloid membrane peeling on pattern and efficiency of transduction of a capsid amino acid substituted AAV2 vector, carrying the green fluorescent protein (GFP) reporter transgene following IVT in dogs. When progressive intraocular inflammation developed starting 4 weeks post IVT, the study plan was modified to allow detailed characterization of the etiology as a secondary goal. Unexpectedly, surgical vitrectomy was found to significantly limit transduction, whereas in non-vitrectomized eyes transduction efficiency reached upwards to 37.3% of RGC layer cells. The developing retinitis was characterized by mononuclear cell infiltrates resulting from a delayed-type hypersensitivity reaction, which we suspect was directed at the GFP transgene. Our results, in a canine large animal model, support caution when considering surgical vitrectomy before IVT for retinal gene therapy in patients, as prior vitrectomy appears to significantly reduce transduction efficiency and may predispose the patient to development of vector-induced immune reactions.
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Studies in large animals (NHP and canine) demonstrate activation of retinal APCs, similar immune cell infiltrates and locally increased levels of classic type 1 cytokines (IFNγ, TNFα, CXCL10) in eyes treated with intravitreal and subretinal AAV vectors.
“This is supported by studies in large animals (NHP and canine) demonstrating activation of retinal APCs, similar immune cell infiltrates and locally increased levels of classic type 1 cytokines (IFNγ , TNFα , CXCL10) in eyes treated with intravitreal and subretinal AAV vectors (Vandenberghe et al., 2011; Boyd et al., 2016; Reichel et al., 2017; Timmers et al., 2020).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Boyd et al., 2016
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References 42 · Cited by 37
- Authors
- Boyd, R. F., Boye, S. L., Conlon, T. J., Erger, K. E., Sledge, D. G., Langohr, I. M., Hauswirth, W. W., Komáromy, A. M., Boye, S. E., Petersen-Jones, S. M., & Bartoe, J. T.
- Affiliations
- Michigan State University (US)
- University of Florida Health (US)
- Venue
- Gene Therapy
- Published
- 2016-04-07
- Volume
- 23
- Issue
- 6
- Pages
- 548-556
- ISSN
- 0969-7128 (ISSN-L)
- 1476-5462
- PMC
- PMC4891289
- OpenAlex
- W2332857514
- Cited by
- 37
- References
- 42
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 6 · 2023: 7 · 2022: 2 · 2021: 6 · 2020: 3 · 2019: 1 · 2018: 1 · 2017: 3 · 2016: 1
- FWCI
- 1.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gene Therapy (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Civil War Book Review (submittedVersion)
- Funders
- Research to Prevent Blindness
- National Institutes of Health
- National Eye Institute (P30EY021721, R24EY022023, R01EY017549, R24EY022012, R01EY024280, R01EY019304)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- adeno-associated virus vectors, intravitreal gene therapy, posterior vitrectomy, vitreous humor, retinal transduction, retinal ganglion cells, glaucoma, GFP reporter, delayed-type hypersensitivity, retinal inflammation, canine model
- MeSH terms
- Dependovirus, Animals, Dogs, Genetic Vectors, Humans, Retina, Transduction, Genetic, Vitrectomy, Transgenes, Green Fluorescent Proteins
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