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M.E. Carrion, M.M. Hamilton, B. Harris, R. King, K. Mori, L.L. Wei; Ocular Pharmacokinetics of Pigment Epithelium–Derived Factor (PEDF) Following Adenovector–Based Gene Delivery Indicate That Low Doses of PEDF Are Therapeutic . Invest. Ophthalmol. Vis. Sci. 2005;46(13):5211.
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Purpose: Pigment epithelium–derived factor (PEDF) is a secreted protein with proven anti–angiogenic and neuroprotective properties, and with prospective application for the treatment of ocular neovascular diseases. PEDF delivery to the retina via adenovector–mediated gene transfer whether by intravitreal or periocular delivery has been shown to inhibit choroidal neovascularization. These experiments were designed to examine PEDF protein levels in ocular tissues following a single intraocular or periocular injection of AdPEDF.11D (a second–generation replication–deficient adenovector) Methods: Adult C57Bl/6 mice were given a single intravitreous or periocular injection of AdPEDF.11D (an E1–/E3–/E4–vector expressing PEDF) into the right eye at doses of 1e9, 1e8, and 1e7 particle units (pu)/eye. Mice were euthanized at 1, 7, and 14–days post vector injection and PEDF levels assessed in the whole eye and various ocular tissues (aqueous humor, cornea, iris/ciliary body, retina, RPE/Choroid, sclera and conjunctiva) using an enzyme–linked immunoabsorbant assay (ELISA). Results: Both intravitreous and periocular delivery resulted in dose–dependent PEDF protein expression. The peak ocular concentration for all doses tested occurred at day one with PEDF expression declining thereafter. The highest dose (1e9 pu) delivered periocularly gave comparable PEDF protein levels to that of the lowest dose (1e7 pu) delivered intravitreally at day one. This is particularly interesting, since the lowest dose of AdPEDF.11D (1e7 pu) administered intravitreously did not result in significant inhibition of choroidal neovascularization in the murine laser–induced rupture of Bruch’s membrane model, yet 1e9 pu AdPEDF. 11D given periocularly resulted in an ∼80% inhibition in this same model (Gehlbach et al, 2003). This observation led us to investigate further the distribution of PEDF levels within various subfractions of the eye, especially the retina, RPE/choroids fraction. Preliminary data suggest that expression of only a small amount of PEDF at the right location is sufficient to inhibit aberrant choroidal neovascularization. Conclusions: Taken together, these data indicate that small amounts of PEDF are sufficient for inhibition of ocular neovascularization and that low doses of AdPEDF.11D may be adequate to provide therapeutic benefit in humans.
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