Pharmacological inhibition of lipofuscin accumulation in the retina as a therapeutic strategy for dry AMD treatment

Age-related macular degeneration (AMD) is the leading cause of blindness in the western world. There is no FDA-approved treatment for the most prevalent dry (atrophic) form of AMD. Photoreceptor degeneration in dry AMD is triggered by abnormalities in the retinal pigment epithelium (RPE). It has been suggested that excessive accumulation of fluorescent lipofuscin pigment in the RPE represents an important pathogenic factor in etiology and progression of dry AMD. Cytotoxic lipofuscin bisretinoids, such as A2E, are formed in the retina in a non-enzymatic way from visual cycle retinoids. Inhibition of toxic bisretinoid production in the retina seems to be a sound treatment strategy for dry AMD. In this review we discuss the following classes of pharmacological treatments inhibiting lipofuscin bisretinoid formation in the retina: direct inhibitors of key visual cycle enzymes, RBP4 antagonists, primary amine-containing aldehyde traps, and deuterated analogs of vitamin A.