Novel Endogenous Glycan Therapy for Retinal Diseases: Safety, In Vitro Stability, Ocular Pharmacokinetic Modeling, and Biodistribution
- 244 Downloads
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 [3H]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 [3H]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.
Key wordsage-related macular degeneration (AMD) NA3 glycan pharmacokinetics safety
The research work was supported by the following grants: March of Dimes, University of Tennessee Research Foundation, International Retinal Research Foundation, an unrestricted grant from Research to Prevent Blindness, Knights Templar Eye Foundation, and Fight for Sight. The authors would like to thank Bob M. Moore, Ph.D. and Vivian S. Loveless, Pharm. D. (Department of Pharmaceutical Sciences, UTHSC) for providing their expertise in radiolabeling and scintillation counting.
- 2.Zhang K, Zhang L, Weinreb RN. Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma. Nat Rev. 2012;11:541–59.Google Scholar
- 6.Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res. 2001;20:705–32.PubMedCrossRefGoogle Scholar
- 20.Swaminathan S, Jablonski MM. Non-biological membranes as drug delivery systems. J Memb Sci Technol. 2012;2(3):e108.Google Scholar
- 22.Jablonski MM, inventor; The University of Tennessee Research Foundation, assignee. Glycan binding proteins as therapeutic targets for retinal disorders and treatment methods based thereon. USA patent 8092825. 2012 Jan 10, 2012.Google Scholar
- 26.Fukuda M. Chemical labeling of carbohydrates by oxidation and sodium borohydride reduction. Curr Protoc Mol Biol. 1994;17.5.1–17.5.8:Supplement 26.Google Scholar
- 29.Bulletin PT. DeadEnd™ Fluorometric TUNEL System: instructions for use of product G3250. Madison, WI, USA.Google Scholar