Novel Endogenous Glycan Therapy for Retinal Diseases: Safety, In Vitro Stability, Ocular Pharmacokinetic Modeling, and Biodistribution

Abstract

Abstract. Asialo, tri-antennary oligosaccharide (NA3 glycan) is an endogenous compound, which supports proper folding of outer segment membranes, promotes normal ultrastructure, and maintains protein expression patterns of photoreceptors and Müller cells in the absence of retinal pigment epithelium support. It is a potential new therapeutic for atrophic age-related macular degeneration (AMD) and other retinal degenerative disorders. Herein, we evaluate the safety, in vitro stability, ocular pharmacokinetics and biodistribution of NA3. NA3 was injected into the vitreous of New Zealand white rabbits at two concentrations viz. 1 nM (minimum effective concentration (MEC)) and 100 nM (100XMEC) at three time points. Safety was evaluated using routine clinical and laboratory tests. Ocular pharmacokinetics and biodistribution of [ 3 H]NA3 were estimated using scintillation counting in various parts of the eye, multiple peripheral organs, and plasma. Pharmacokinetic parameters were estimated by non-compartmental modeling. A 2-aminobenzamide labeling and hydrophilic interaction liquid interaction chromatography were used to assess plasma and vitreous stability. NA3 was well tolerated by the eye. The concentration of NA3 in eye tissues was in the order: vitreous>retina>sclera/choroid> aqueous humor>cornea>lens. Area under the curve (0 to infinity) (AUC∞) was the highest in the vitreous thereby providing a positive concentration gradient for NA3 to reach the retina. Half-lives in critical eye tissues ranged between 40 and 60 h. NA3 concentrations were negligible in peripheral organs. Radioactivity from [ 3 H]NA3 was excreted via urine and feces. NA3 was stable at 37°C in vitreous over a minimum of 6 days, while it degraded rapidly in plasma. Collectively, these results document that NA3 shows a good safety profile and favorable ocular pharmacokinetics.

Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility

“…For each mouse, the tested ophthalmic formulation (10 μl) was applied to the right eye, while the left eye received the blank and serve as a control 29 , 60 . One hundred microliters of 0.9% pregabalin eye drops were applied into the inferior conjunctival sac of the right eye of the Dutch belted rabbits, while the left eye received the blank eye drops 61 . All results were expressed as the mean percentage reduction in IOP from baseline (mean% reduction ± SEM).…”

N-Glycosylation Patterns across the Age-Related Macular Degeneration Spectrum

“…The interest in exploring N -glycans’ role in AMD stems from the understanding that various proteoglycans have a role in retinal development and functioning [ 20 , 21 , 22 ], suggesting that their manipulation may even have beneficial therapeutic effects [ 23 ]. This was seen for NA3, a tri-antennary glycan without sialic acid, which was implied as having a protective role in AMD pathogenesis [ 24 , 25 ]. Furthermore, more complex structures and interactions between various classes of biological molecules such as lipids, proteins, and glycans might affect AMD development and prognosis [ 24 , 26 , 27 ].…”