High‐Density Lipoprotein Engineering for Eye‐Drop Treatment of Age‐Related Macular Degeneration

Abstract

Eye-drop treatments of age-related macular degeneration (AMD) are desirable; however, no clinically approved eye drop has been reported to date. This study aim to evaluate the therapeutic activity of eye-drop instillation of a high-density lipoprotein (HDL) variant bearing a cell-penetrating peptide and neovasculature-targeted peptide (AsnGlyArg [NGR] peptide) in a mouse model at a dose of 0.6–0.85 µg protein/eye drop. The results reveal that the activity of the abovementioned variant was >10-fold higher than that of the previous variant lacking an NGR peptide. In addition, the anti-inflammatory activity, cholesterol-efflux capacity, and antiangiogenic activity of reconstituted HDL are significantly augmented by the attachment of these two peptides. The mechanism underlying this dramatic improvement is likely the expression of CD13, an NGR peptide receptor, on the cornea and conjunctiva in mice. CD13 mRNA/protein expression is also detected in cultured human corneal and conjunctival cells. These results demonstrate that NGR peptide is an unprecedented class of an absorption enhancer on the eye surface. Thus, HDL engineering is a potential strategy for developing eye drops to treat neovascular AMD by enhancing the ocular surface absorption and HDL functionalities.