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HS Rasmussen, WH Bee, MC Wills, RJ Munger, RJ Durham, LL Wei; Safety of Intravitreal Delivery of Adenovirusin Cynomolgus Monkeys . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1289.
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Purpose: Gene transfer offers a novel treatment for many types of ocular diseases. Adenovirus appears to be an efficient vector for delivery of therapeutic genes such as Pigment Epithelium-Derived Factor (PEDF). Studies were performed in Cynomolgus monkeys to evaluate the safety of intravitreal delivery of a second generation E1-, E4- and partial E3 deleted replication deficient vector, AdPEDF, as well as identify dose-limiting toxicity (DLT). Methods: Single invitreous injections of 1 x 108,1 x 109,1 x 1010, and 5 x 1010 particles (pu) and multiple injections of 1 x 109 were performed in one eye of 22 primates. No treatment or a comparable volume (50µl) of saline or vehicle was delivered to the contralateral eye. Safety was assessed by direct and indirect ophthalmologic examinations, electroretinography (ERG), tonometry, histopathology of the eye and observations of gross anatomy at necropsy. Results: Our findings showed no toxicity at the dose level of 1 x 108 pu (no adverse effect dose). At higher doses, dose-dependent inflammatory responses, ranging from minimal and reversible at a dose of 1 x 109 pu to moderate at a dose of 1 x 1010 pu and marked at a dose level of 5 x 1010 pu were observed. ERG responses were normal with doses of 1 x 108 pu and 1 x 109 pu. All control eyes were within normal limits. No systemic toxicities were observed at any dose level. Conclusion: Doses of 1 x 108 pu and 1 x 109 pu appear to be well tolerated in the monkey eye even after repeat dosing. Higher doses at 1 x 1010 pu and 5 x 1010 pu resulted in increasing levels of inflammation, the dose-limiting toxicity. These data identify a range of potential safe doses for a Phase I human clinical trial and methods to monitor for any potential adverse reactions; such a trial is currently being planned.
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