Simian Immunodeficiency Virus-Based Lentivirus Vector for Retinal Gene Transfer: A Preclinical Safety Study in Adult Rats
Abstract
Although lentivirus vectors hold promise for ocular gene therapy, they also have potential safety issues, particularly in the case of the current human immunodeficiency virus-based vectors. We recently developed a novel lentivirus vector derived from the nonpathogenic simian immunodeficiency virus from African green monkeys (SIVagm) to minimize these potentials. In this preclinical study, we evaluated whether SIV vector could be efficiently and safely applicable to retinal gene transfer by assessing the transgene expression, retinal function and histology over a 1-year period following subretinal injection in adult rats. The functional assessment via electroretinogram after both titers of SIV-lacZ (2.5 x 10(7) or 2.5 x 10(8) transducing units/ml) injection revealed both the dark and light adaptations to soon be impaired, in a dose-dependent manner, after a buffer injection as well, and all of them recovered to the control range by day 30. In both titers tested, the retinas demonstrated a frequent transgene expression mainly in the retinal pigment epithelium; however, the other retinal cells rarely expressed the transgene. Retinas exposed to a low titer virus showed no significant inflammatory reaction throughout the observation period, and also maintained the transgene expression over a 1-year period. In the retinas exposed to a high titer virus, however, mononuclear cell infiltration persisted in the subretinal area, and the retina that corresponded to the injected area finally underwent degeneration by around day 90. No retinal neoplastic lesions could be found in any animals over the 1-year period. We thus propose that SIV-mediated stable gene transfer might be useful for ocular gene transfer; however, more attention should be paid to avoiding complications when administering high titer lentivirus to the retina.
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In adult Male Wistar rats, low-dose SIV vector injected subretinally produced no inflammatory reaction by histology and stable long-term transgene expression persisting over 1 year, while high-dose SIV vector produced mononuclear cell infiltration in the subretinal area.
“In a study aimed at evaluating the efficiency and safety of SIV vectors, a SIV vector was injected subretinally in adult Male Wistar rats at a low (2.5 × 10 7 TU/mL, TU: transducing unit) or high (2.5 × 10 8 TU/mL) dose.In the low dose group, no inflammatory reaction was observed by histology examinations, and this was accompanied by a stable long-term transgene expression which persisted over 1”
From Immune responses to gene editing by viral and non-viral delivery vectors used in retinal gene therapy (2022) · cites this paper as [58]
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- Authors
- Ikeda, Y., Goto, Y., Yonemitsu, Y., Miyazaki, M., Sakamoto, T., Ishibashi, T., Tabata, T., Ueda, Y., Hasegawa, M., Tobimatsu, S., & Sueishi, K.
- Affiliations
- Kyushu University (JP)
- Kagoshima University (JP)
- ID Pharma (Japan) (JP)
- Venue
- Gene Therapy
- Published
- 2003-06-30
- Volume
- 10
- Issue
- 14
- Pages
- 1161-1169
- ISSN
- 0969-7128 (ISSN-L)
- 1476-5462
- OpenAlex
- W2016450624
- Cited by
- 30
- References
- 32
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2022: 1 · 2021: 1 · 2016: 2 · 2014: 1 · 2013: 1
- FWCI
- 1.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Gene Therapy (publishedVersion)
- PubMed (publishedVersion)
- 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
- simian immunodeficiency virus, lentiviral vectors, retinal gene transfer, ocular gene therapy, vector safety, subretinal injection, electroretinogram, retinal function, retinal pigment epithelium, mononuclear cell infiltration, retinal degeneration, transgene expression, chronic toxicity, vervet monkey
- MeSH terms
- Animals, Electroretinography, Genetic Vectors, Injections, Luminescent Proteins, Male, Necrosis, Retina, Retinal Diseases, Time Factors, Simian Immunodeficiency Virus, Genetic Therapy, Gene Expression, Rats, Wistar, Transgenes, Models, Animal, Green Fluorescent Proteins, Rats
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