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L.L. Wei, M. Hamilton, C.R. King, D. McVey, D. Brough; All Trans–Retinoic Acid Regulation of Transgene Expression in the Eye . Invest. Ophthalmol. Vis. Sci. 2006;47(13):835.
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To determine parameters for transgene re–expression using all trans–retinoic acid (ATRA) in the eye following a single intravitreal (IVT) injection of an adenovector protein expression system.
To assess the feasibility and determine parameters for use of ATRA for transgene re–expression. C57Bl/6 mice received a single IVT injection of AdLuciferase.11D –AdL.11D (1e9 particle units) at Day 0. Animals received a single intramuscular (IM), oral or topical dose of ATRA (1mM) on either day 28 or 59 post–vector injection. Animals were sacrificed 24 hours post– ATRA injections, eyes enucleated, and assayed for luciferase activity. To determine whether transgene re–expression could be repeated within the same animal, animals received a single IVT injection of AdL.11D (1e9 particle units) at Day 0. ATRA (1 mM) was administered on Day 28 and Day 59 as a single IM dose. Animals were sacrificed 24 hours post– ATRA injections, eyes enucleated, and assayed.
These studies demonstrate: 1) that transgene expression can be up–regulated by a small molecule, ATRA, in the mouse eye at a time when transgene expression is low after a single adenoviral vector delivery; 2) re–expression is possible at multiple time points post–adenoviral administration and re–expression can be induced at least twice in the same eye; and 3) ATRA stimulated re–expression can be obtained via several routes of delivery.
These preliminary results suggest a promising way to turn on gene expression from an adenoviral protein expression system within the eye without repeated intravitreal administrations. Conventional delivery routes using a small molecule, ATRA, make this a new alternative approach to treating ocular diseases.
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