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L. L. Wei, M. M. Hamilton, J. G. Gall, D. E. Brough, C. R. King; Alternate Serotype Adenovector Gives Long-Term Expression in the Eye. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5803.
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In the last 5 years, treatment of ocular neovascular diseases has become available, in particular for wet age-related macular degeneration (AMD). Two novel methods for the treatment of wet AMD have emerged and conclusively demonstrate that inhibition of VEGF in the eye is safe and effective. However, despite the clear efficacy and safety of these treatments, there continues to be a medical need for less frequent and less invasive intraocular delivery into the eye. One novel strategy is to use gene delivery systems, alternate serotypes of adenovirus, that enable the synthesis of anti-angiogenic agents in the eye over several months. To develop improved adenovectors, we compared the performance of two different adenovector serotypes, Ad5 and Ad35. Ad35 shares many of the advantages of other adenovectors such as ability to transduce non-dividing cells, growth to high titers in vitro and large carrying capacity. The purpose of this study was to determine whether the duration of transgene expression from an alternate adenovector serotype, Ad35, would provide advantages over the well-studied Ad5 serotype vector following a single intravitreal administration in the eye.
Adult C57BL/6 mice were given a single intravitreous injection (1 x 109 particle units /eye) of Ad5 and Ad35 vectors that express Green Fluorescent Protein (GFP). Negative controls included naïve animals and animals injected with adenovector diluent intravitreally. At various times after vector administration, eyes of animals were monitored visually for the presence of GFP and recorded by digital photography. We utilized a minimum of 5 animals per group per time point. Time points where GFP signal was monitored and recorded were Day 1, 7, 14, 28, and Month 2, 3, 4 and 8.
With the Ad5GFP vector we find a rapid induction in GFP signal within 24 hours post-injection into the eye. Subsequent to Day 7, GFP levels rapidly decline in eyes administered Ad5GFP. In contrast, the response with the Ad35 vector results in some GFP signal on Day 1, which gradually increases in intensity with time. By Day 28 the signal exceeds that observed on Day 1 for Ad5 treated animals. The GFP signal continues beyond 4 months in the Ad35 treated eyes and then diminishes by around 8 months.
These initial studies indicate that an alternate adenovector serotype, Ad35, may provide much longer-term transgene expression than Ad5 vectors. Future studies will attempt to determine whether a single, intravitreal injection of an Ad35 vector with a therapeutic gene product will also result in elevated levels for extended periods of time.
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