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Published on: May 6, 2015
Adenovirus serotype 35 vector-mediated transduction following direct administration into organs of nonhuman primates
F Sakurai1, S-i Nakamura, K Akitomo
1Laboratory of Gene Transfer and Regulation, National Institute of Biomedical Innovation, Ibaraki City, Osaka, Japan.
Abstract:
Adenovirus (Ad) serotype 35 (Ad35) vectors have attracted remarkable attention as alternatives to conventional Ad serotype 5 (Ad5) vectors. In a previous study, we showed that intravenously administered Ad35 vectors exhibited a safer profile than Ad5 vectors in cynomolgus monkeys, which ubiquitously express CD46, an Ad35 receptor, in a pattern similar to that in humans. However, the Ad35 vectors poorly transduced the organs. In this study, we examined the transduction properties of Ad35 vectors after local administration into organs of cynomolgus monkeys. The vectors transduced different types of cells depending on the organ. Hepatocytes and microglia were mainly transduced after the vectors were injected into the liver and cerebrum, respectively. Injection of the vectors into the femoral muscle resulted in the transduction of cells that appeared to be fibroblasts and/or macrophages. Conjunctival epithelial cells showed transgene expression following infusion into the vitreous body of the eyeball. Transgene expression was limited to areas around the injection points in most of the organs. In contrast, Ad35 vector-mediated transgene expression was not detected in any of the organs not injected with Ad35 vectors. These results suggest that Ad35 vectors are suitable for gene delivery by direct administration to organs.
Insights
Adenovirus 35 (Ad35) vectors show targeted gene delivery in organs after direct administration in monkeys. Local Ad35 vector injection successfully transduced specific cells, unlike intravenous delivery.
Area of Science:
- Gene therapy
- Viral vector technology
- Primate models
Background:
- Adenovirus serotype 5 (Ad5) vectors are common but have limitations.
- Adenovirus serotype 35 (Ad35) vectors offer a safer alternative, particularly in humans and cynomolgus monkeys expressing CD46.
- Previous studies showed poor organ transduction with intravenous Ad35 vector administration.
Purpose of the Study:
- To evaluate the transduction efficiency of Ad35 vectors following local administration into various organs.
- To determine the cell types transduced by Ad35 vectors in different organs after direct injection.
- To assess the feasibility of Ad35 vectors for targeted organ gene delivery.
Main Methods:
- Local administration of Ad35 vectors into the liver, cerebrum, femoral muscle, and vitreous body of cynomolgus monkey eyes.
- Analysis of transgene expression in injected and non-injected organs.
- Histological examination to identify transduced cell types.
Main Results:
- Ad35 vectors transduced specific cell types depending on the organ: hepatocytes (liver), microglia (cerebrum), fibroblasts/macrophages (muscle), and conjunctival epithelial cells (eye).
- Transgene expression was localized to the injection sites in most organs.
- No detectable transgene expression occurred in organs not directly injected with Ad35 vectors.
Conclusions:
- Local administration of Ad35 vectors enables targeted gene delivery to specific organs.
- Ad35 vectors demonstrate potential for localized gene therapy applications via direct organ injection.
- This approach overcomes the limitations of poor organ transduction observed with systemic administration.
