Dosage thresholds for AAV2 and AAV8 photoreceptor gene therapy in monkey
Open accessAbstract
AAV2 and AAV8 viral vectors administered subretinally transduce retinal pigment epithelium and photoreceptors in monkey.
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An immune response to viruses and antibody generation is a sign of a healthy functioning immune system, so serum antibodies are not a cause for concern unless they cause inflammation.
“An immune response to viruses and the generation of antibodies is a sign of a healthy functioning immune system, so the serum antibodies are not a cause for concern unless they cause inflammation.11,21,40,41”
From Systemic and local immune responses to intraocular AAV vector administration in non-human primates (2022) · cites this paper as [40]
The Results section, “Immune responses to GFP and the AAV capsid” (page unavailable), reports that AAV administration increased neutralizing antibodies, especially in serum. The Discussion (page unavailable) treats immune responses as a safety concern and describes retinal inflammation in some animals; it does not say that antibody generation indicates a healthy immune system or that serum antibodies are harmless unless they cause inflammation. (LLM, conf=0.83)
Experimental — accuracy not yet measuredStudies 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 Vandenberghe et al., 2011
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Experimental — accuracy not yet measuredHigher vector doses have been shown to enhance transduction efficiency.
“In addition, higher vector doses have been shown to enhance transduction efficiency (Vandenberghe et al., 2011).”
From AAV2 and AAV9 tropism and transgene expression in the mouse eye and major tissues after intravitreal and subretinal delivery (2023) · cites this paper as Vandenberghe et al., 2011
The transduction efficiency of AAV8 in photoreceptors and RPE was found to be superior to that of AAV2.
“In fact, the transduction efficiency of AAV8 in photoreceptors and RPE was found to be superior to that of AAV260.”
From An adeno-associated virus variant enabling efficient ocular-directed gene delivery across species (2024) · cites this paper as [60]
Subretinal injections for viral gene therapy may trigger host immune responses.
“Subretinal injections for viral gene therapy may trigger host immune responses [258,288,289,290,291]”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [289]
In NHPs, high doses of AAV2 or AAV8 carrying GFP delivered by subretinal injection resulted in an increase in anti-AAV antibodies, a systemic T-cell response to the transgene, and retinal damage characterized by loss of photoreceptors.
“High doses resulted in an increase in anti-AAV antibodies, a systemic T-cell response to the transgene and retinal damage characterized by a loss of photoreceptors [52].”
From Immune responses to gene editing by viral and non-viral delivery vectors used in retinal gene therapy (2022) · cites this paper as [52]
Several studies have shown that the dose of the vector administered influences the immune outcome.
“Several studies have shown that the dose of the vector administered influences the immune outcome.”
From Immune responses to gene editing by viral and non-viral delivery vectors used in retinal gene therapy (2022) · cites this paper as [52]
An increase in dose implies an increase in vector, transgene and promoter, each of which has independently and cumulatively shown to affect immune responses.
“An increase in dose implies an increase in vector, transgene and promoter-each of which has independently and cumulatively shown to affect immune responses [30,52,86,87].”
From Immune responses to gene editing by viral and non-viral delivery vectors used in retinal gene therapy (2022) · cites this paper as [52]
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References 35 · Cited by 242
- Authors
- Vandenberghe, L. H., Bell, P., Maguire, A. M., Cearley, C. N., Xiao, R., Calcedo, R., Wang, L., Castle, M. J., Maguire, A. C., Grant, R., Wolfe, J. H., Wilson, J. M., & Bennett, J.
- Affiliations
- Children's Hospital of Philadelphia (US)
- University of Pennsylvania (US)
- Corresponding author
- Vandenberghe, Luk H.
- Maguire, Alexandra C.
- Wilson, James M.
- Bennett, Jean
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2011-06-22
- Volume
- 3
- Issue
- 88
- Pages
- 88ra54-88ra54
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC5027886
- OpenAlex
- W2123950745
- Cited by
- 242
- References
- 35
- Citations by year
- 2026: 14 · 2025: 20 · 2024: 20 · 2023: 18 · 2022: 14 · 2021: 14 · 2020: 18 · 2019: 10 · 2018: 21 · 2017: 19 · 2016: 11 · 2015: 11 · 2014: 18 · 2013: 16 · 2012: 13
- FWCI
- 10.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (T32NS007180, R01NS038690, NS-007180, NS-007413, NS038690, T32NS007413)
- National Center for Research Resources (UL1RR024134)
- 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, AAV2, AAV8, retinal degeneration, dose-response relationship, vector targeting, retinal pigment epithelium, subretinal injection, non-human primates, transgene expression, immunogenicity, retinal gene therapy
- MeSH terms
- Dependovirus, Animals, Female, Genetic Vectors, Humans, Macaca, Male, Photoreceptor Cells, Retina, Retinal Degeneration, Transduction, Genetic, Genetic Therapy, Genes, Reporter, Transgenes, Green Fluorescent Proteins
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