Cited by 203Virus-based gene therapy researchRetinal Development and DisordersRNA Interference and Gene Delivery

Recombinant adeno-associated virus serotype 4 mediates unique and exclusive long-term transduction of retinal pigmented epithelium in rat, dog, and nonhuman primate after subretinal delivery

Open access
Weber, Michel, Rabinowitz, Joseph, Provost, Nathalie, Conrath, Hervé, Folliot, Sébastien, Briot, Delphine, Chérel, Yan, Chenuaud, Pierre +3 more·2003·Molecular Therapy

Abstract

We previously described chimeric recombinant adeno-associated virus (rAAV) vectors 2/4 and 2/5 as the most efficient vectors in rat retina. We now characterize these two vectors carrying the CMV.gfp genome following subretinal injection in the Wistar rat, beagle dog, and cynomolgus macaque. Both serotypes displayed stable GFP expression for the duration of the experiment (6 months) in all three animal models. Similar to the AAV-2 serotype, AAV-2/5 transduced both RPE and photoreceptor cells, with higher level of transduction in photoreceptors, whereas rAAV-2/4 transduction was unambiguously restricted to RPE cells. This unique specificity found conserved among all three species makes AAV-2/4-derived vectors attractive for retinal diseases originating in RPE such as Leber congenital amaurosis (RPE65) or retinitis pigmentosa due to a mutated mertk gene. To provide further important preclinical data, vector shedding was monitored by PCR in various biological fluids for 2 months post-rAAV administration. Following rAAV-2/4 and -5 subretinal delivery in dogs (n = 6) and in nonhuman primates (n = 2), vector genome was found in lacrymal and nasal fluids for up to 3-4 days and in the serum for up to 15-20 days. Overall, these findings will have a practical impact on the development of future gene therapy trials of retinal diseases.

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Crossref · 10.1016/s1525-0016(03)00098-4

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  • Such exposure can lead to transient expression of gene products in blood or formation of granulomas where cells are in contact with choroidal circulation.

    “Such an exposure can lead to a transient expression of gene products in blood or the formation of granulomas where cells are in contact with choroidal circulation (35, 36).”
  • The two-step procedure increases the risk of retinotomy enlargement leading to more reflux, and for this reason a one-step approach has been favored in many clinical trials.

    “Two-step procedure increases the risk of having the retinotomy enlarge leading to more reflux, for this reason, a one-step approach has been favored in many clinical trials (34–36).”

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Authors
Weber, M., Rabinowitz, J., Provost, N., Conrath, H., Folliot, S., Briot, D., Chérel, Y., Chenuaud, P., Samulski, J., Moullier, P., & Rolling, F.
Affiliations
  • Inserm (FR)
  • University of North Carolina at Chapel Hill (US)
  • Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
Corresponding author
Rolling, Fabienne
Venue
Molecular Therapy
Publisher
Elsevier BV
Published
2003-06
Volume
7
Issue
6
Pages
774-781
ISSN
1525-0016 (ISSN-L)
OpenAlex
W2162857177
Cited by
203
References
47
Citations by year
2026: 1 · 2025: 4 · 2024: 6 · 2023: 6 · 2022: 4 · 2021: 5 · 2020: 9 · 2019: 5 · 2018: 3 · 2017: 8 · 2016: 1 · 2015: 12 · 2014: 12 · 2013: 9 · 2012: 13
FWCI
7.58
Type
journal article
Language
en
Open access
Locations
  • Molecular Therapy (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • HAL (submittedVersion)
  • UNC Libraries
Funders
  • Lions Clubs International Foundation
  • Institut National de la Santé et de la Recherche Médicale
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
recombinant adeno-associated virus, retinal pigment epithelium, subretinal gene delivery, retinal transduction, photoreceptors, non-human primates, dogs, rats, Leber congenital amaurosis, retinitis pigmentosa, MERTK, gene therapy vectors
MeSH terms
Dependovirus, Animals, Cells, Cultured, Cytomegalovirus, Defective Viruses, DNA, Recombinant, Dogs, Gene Expression Regulation, Genetic Vectors, Luminescent Proteins, Macaca fascicularis, Pigment Epithelium of Eye, Transduction, Genetic, Polymerase Chain Reaction, Rats, Wistar, Transgenes, Photoreceptor Cells, Vertebrate, Green Fluorescent Proteins, Rats

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