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Shankar Swaminathan, Huiling Li, Mallika Palamoor, Dorababu Madhura, Bernd Meibohm, Monica Jablonski; A Novel Endogenous Glycan Therapy For Retinal Diseases: Safety, In vitro Stability, Ocular Pharmacokinetics and Bio-distribution. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3273.
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Asialo tri-antennary oligosaccharide (NA3 glycan) is a novel endogenous compound which supports the proper folding of outer segment membranes; promotes normal ultrastructure and maintains protein expression patterns of photoreceptors and Müller cells in the absence of RPE support. Hence it is a potential new therapeutic for atrophic AMD. Our purpose was to evaluate the safety, in vitro stability, ocular pharmacokinetics and biodistribution of NA3 in the eye.
NA3 was injected into the vitreous of NZW rabbits at two concentrations viz. 1 nM (MEC) and 100 nM (100XMEC) at three time points (1d-14d). Safety was evaluated using routine clinical and laboratory tests. NA3 was tagged with tritium. Ocular pharmacokinetics and biodistribution were estimated at predetermined time points (2h-14d). Rabbits were sacrificed and various parts of the eye, multiple peripheral organs and plasma were isolated. NA3 was quantified using scintillation counting. Pharmacokinetics was estimated by non-compartmental modeling (WinNonlin 6.2). A 2-aminobenzamide labeling method and subsequent HILIC chromatographic separation were used to assess plasma and vitreous stability at simulated biological conditions.
NA3 was well tolerated by the eye. The concentration of NA3 in various eye tissues was in the following order: vitreous>retina>sclera/choroid>aqueous humor>cornea>lens. AUC∞ was maximum in the vitreous thereby providing a positive concentration gradient for the drug to reach the retina. Half-lives in critical eye tissues were between 40-60 h. NA3 concentrations were negligible in peripheral organs. Radioactivity from tritiated NA3 was excreted via urine and feces. By using an optimized HILIC method with fluorescence detection, NA3 was found to be stable at 37°C in excised vitreous over a minimum of 6 days, while it degraded within a few hours in plasma thereby providing a breakthrough targeted therapy for atrophic AMD and other retinal diseases.
NA3 glycan is safe for intraocular applications, degrades rapidly in plasma with minimal organ distribution, while being stable in vitreous. Ocular pharmacokinetics confirms the movement of NA3 from vitreous to retina, the site of action. With novel formulation strategies, the residence time of NA3 would be increased for therapeutic applications in chronic retinal diseases.
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