Age-related macular degeneration (AMD) is the predominant cause of blindness in the United States. Lipofuscin accumulation in the retina, which increases with age, is implicated in the pathogenesis of dry AMD. Pyridinium bisretinoids constitute the primary cytotoxic elements of retinal lipofuscin. Inhibiting bisretinoid synthesis is a viable approach for treating dry AMD. The synthesis of bisretinoids is driven by the traffic of retinol from the bloodstream to the retina. The RBP4-Transthyretin (TTR) complex acts as the primary carrier for delivering retinol to the eye. RBP4 antagonists displace retinol from RBP4, causing the RBP4-Transthyretin (TTR) complex to dissociate. This reduces retinol transport to the eye and suppresses lipofuscin bisretinoid synthesis in the retina. Fenretinide, a first-generation RBP4 antagonist, suppressed the expansion of atrophic lesions in dry AMD patients when serum RBP4 levels fell below the 1-micromolar threshold. However, selective RBP4 antagonists, by disrupting the RBP4-TTR interaction, could potentially destabilize wild-type TTR tetramers promoting TTR aggregation in individuals with age-related predisposition to TTR amyloidosis disease. We have recently introduced a novel class of bispecific RBP4/TTR ligands. These compounds not only reduce serum RBP4 levels and suppress bisretinoid synthesis but also bind to the thyroxine binding sites on TTR. This binding stabilizes TTR tetramers and prevents the formation of TTR amyloids. (R)-ACPHS-62, an optimized bispecific RBP4/TTR ligand, emerged as a drug candidate for treatment of dry AMD in individuals with age-related predisposition to TTR amyloidosis. The proposed project has two main objectives: first, to perform experiments required to progress (R)-ACPHS-62 towards GLP-compliant IND-enabling studies (Aim 1; R61 phase); and second, to carry out GLP-compliant IND-enabling studies and submit the IND application (Aim 2; R33 phase).