The Role of Dopaminergic Agonists in Geographic Atrophy: Converging Evidence From Clinical and Experimental Data

Purpose: Levodopa (L-DOPA) is an emerging drug repurposing candidate for age-related macular degeneration (AMD). Basic and clinical studies identify a potential role for L-DOPA to prevent and treat neovascular AMD. However, only one prior study has been performed in geographic atrophy (GA). Methods: We performed a retrospective cohort analysis from the Sight Outcomes Research Collaborative database, including eyes with a diagnosis of early- or intermediate-stage AMD in 1 eye. We compared eyes exposed to any dopamine agonist (DA), dopamine receptor D2 agonist, and L-DOPA with eyes with no DA exposure using propensity score matching and survival analysis with multivariable Cox proportional hazard models with new GA development as our primary outcome. Mice were treated with intraperitoneal NaIO3 to induce GA-like pathology. We compared L-DOPA with phosphate-buffered saline-treated controls in both pigmented and albino mice. We quantified retinal thickness by optical coherence tomography, and performed immunofluorescence to quantify choriocapillaris and retinal pigment epithelium density. Results: Any DA, dopamine receptor D2, and L-DOPA exposure were not associated with new-onset GA. NaIO3 treatment caused retinal thinning, choriocapillaris loss, and retinal pigment epithelium degeneration, which were not rescued by L-DOPA treatment in pigmented nor albino mice. Conclusions: In both retrospective database analysis and preclinical models, DA had no effect upon GA pathology. Translational Relevance: Further investigation of levodopa may be more appropriately directed toward neovascular age-related macular degeneration, rather than geographic atrophy, where preclinical, retrospective, epidemiologic, and prospective data suggest a benefit.