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D.L. McVey, L.L. Wei, C. Hsu, M. Hamilton, C. King, D.E. Brough; Adenoviral Gene Delivery for the Treatment of Ocular Diseases . Invest. Ophthalmol. Vis. Sci. 2003;44(13):444.
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Purpose: Adenoviral vectors expressing PEDF have been shown to be efficacious in preclinical models of age-related macular degeneration and diabetic retinopathy. In these studies an adenoviral vector deleted in the E1, E3, and E4 regions expressing PEDF from a CMV promoter was used. We have demonstrated that expression of PEDF from this vector is transient with peak levels achieved at day one rapidly declining to undetectable levels in 14 days. In the current studies we set out to determine if changing the promoter could increase the persistence of transgene expression from adenovirus vectors delivered intravitreally into the eye. Methods: In this study, replication-deficient adenovirus vectors were generated that differed only by incorporation of different promoters upstream of a luciferase marker gene. Intravitreal injections were made into mouse eyes in a total volume of 2 ul to deliver a dose of between 1e7 and 1e9 total vector particles. Luciferase levels were monitored on days 1, 14 and 28. Results/Conclusions: The highest initial level of protein expression was observed when the CMV promoter is driving protein expression. Three different expression profiles were defined in which expression either decreased, remained relatively stable or increased with time. These results indicate that alteration of the promoter contained within an adenovirus vector can result in prolonged expression of a transgene following intravitreal delivery. This may allow for the construction of adenovirus vectors with prolonged expression of anti-angiogenic factors such as PEDF.
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