Safety and efficacy of subretinal readministration of a viral vector in large animals to treat congenital blindness
Open accessAbstract
After successful gene therapy to correct retinal degeneration in one eye, treatment of the second eye is safe and effective—even when immunity to the vector is present—in nonhuman primates and dogs.
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AAV administration to immune privileged regions can lead to increases in neutralizing antibody titers, including after intravitreal injection in dogs and NHPs and intracranial injections in clinical trials.
“Furthermore, AAV administration to immune privileged regions can lead to increases in neutralizing antibody titers, including following intravitreal injection in dogs and non-human primates37 and following intracranial injections in several clinical trials.38”
From Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates (2015) · cites this paper as [37]
The Results sections on immune responses in dogs and NHPs report increased AAV2 neutralizing-antibody titers after ocular vector administration. But the Results section on bilateral readministration specifies that the vector was injected subretinally, not intravitreally; the intravitreal injection mentioned there was ciprofloxacin. The intracranial-trial clause is attached to a different citation and is not assessed here. (LLM, conf=0.90)
Experimental — accuracy not yet measuredAAV serotype, virus dose, re-administration, promoter, and transgene can influence immune responses to ocular AAV gene delivery.
“Other factors that can influence the immune responses are the AAV serotype used,18 the virus dose injected,19 whether the injection is re-administrated,20 and the promoter21,22 and transgene used.23”
From Systemic and local immune responses to intraocular AAV vector administration in non-human primates (2022) · cites this paper as [20]
Prior studies reported that subretinal AAV vector injections in dogs and non-human primates, and some intracranial injections in clinical trials, increased serum anti-AAV antibody titers.
“This observation is consistent with previous reports that subretinal injections of AAV vectors in dogs and non-human primates,37 as well as some intracranial injections in several clinical trials,38 led to increased serum anti-AAV antibody titers.”
From Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates (2015) · cites this paper as [37]
AAV vectors are less susceptible to antibody neutralisation within a more immune privileged space.
“AAV vectors are also less susceptible to antibody neutralisation within a more immune privileged space (Li et al., 2008; Amado et al., 2010).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Amado et al., 2010
The effectiveness of subretinal gene therapy does not seem to be affected by the presence of neutralising antibodies in the host serum.
“the effectiveness of subretinal gene therapy does not seem to be affected by the presence of neutralising antibodies in the host serum [287].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [287]
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References 37 · Cited by 140
Research works printed but not linked: 1
- [19]Muzyczka N Berns K Knipe D Howley P Fields Virology 2001 2 2327 2359 Lippincott Williams & Wilkins Philadelphia
- Authors
- Amado, D., Mingozzi, F., Hui, D., Bennicelli, J. L., Wei, Z., Chen, Y., Bote, E., Grant, R. L., Golden, J. A., Narfstrom, K., Syed, N. A., Orlin, S. E., High, K. A., Maguire, A. M., & Bennett, J.
- Affiliations
- University of Pennsylvania (US)
- Children's Hospital of Philadelphia (US)
- Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia, Abramson Pediatric Research Center, Philadelphia, PA 19014, USA.
- College of Veterinary Medicine and Mason Eye Institute, University of Missouri-Columbia, Columbia, MO 65212, USA.
- University of Iowa (US)
- Corresponding author
- Amado, Defne
- Mingozzi, Federico
- Bennett, Jean
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2010-03-03
- Volume
- 2
- Issue
- 21
- Pages
- 21ra16-21ra16
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC4169124
- OpenAlex
- W2077204087
- Cited by
- 140
- References
- 37
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 7 · 2023: 7 · 2022: 6 · 2021: 7 · 2020: 12 · 2019: 5 · 2018: 8 · 2017: 16 · 2016: 8 · 2015: 10 · 2014: 10 · 2013: 9 · 2012: 11
- FWCI
- 3.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5f30ag030961-02)
- National Institute on Aging (1F30AG030961, F30 AG030961)
- National Eye Institute (P30EY001583)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- Leber congenital amaurosis, RPE65 mutations, subretinal gene therapy, fellow eye, neutralizing antibodies, cell-mediated immunity, CD4+ T cells, retinal degeneration, visual recovery, large animal model
- MeSH terms
- Retinoid Isomerohydrolase, Dependovirus, Adult, Aged, Aged, 80 and over, Animals, Anterior Chamber, Blindness, Capsid, Carrier Proteins, Dogs, Drug Administration Routes, Eye Proteins, Genetic Vectors, Humans, Immunity, Immunohistochemistry, Middle Aged, Postmortem Changes, Primates, Retina, Genetic Therapy, Treatment Outcome, Titrimetry, cis-trans-Isomerases, Antibodies, Neutralizing
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