Therapy for macular degeneration: Insights from acne

Individuals with Stargardt's disease can navigate a crowd by using peripheral vision, but reading and recognizing faces can be onerous and shapes and contours may appear distorted. This progressive and devastating visual impairment reflects the loss of light-absorbing photoreceptor cells in the central area of the retina (macula), which is typical of this juvenile form of macular degeneration (1). Yet to understand the cause of photoreceptor cell degeneration in Stargardt's macular degeneration it is necessary to take into account the retinal pigment epithelium (RPE), a cell layer lying adjacent to the photoreceptor cells. Because the RPE is vital to the integrity of the photoreceptor cells, the demise of RPE cells brings about the loss of photoreceptors (2).

Studies performed over the past several years have pointed to the fluorophores that constitute the lipofuscin of RPE cells as being crucial factors in the degeneration of these cells in macular degeneration. Of added importance is the fact that lipofuscin is not just a feature of the Stargardt's disease; it also accumulates with age in the RPE cells of all eyes (3). Much of this indigestible pigment originates in the photoreceptor cell, with deposition in the RPE occurring because it is the responsibility of the RPE to internalize membranous debris discarded daily by the photoreceptor cell. Characterization of the composition of RPE lipofuscin has revealed that a major constitutent is A2E, a conjugate of vitamin A aldehyde (4–6). A2E has a pyridinium bisretinoid structure that is unprecedented (7) and once formed it cannot be enzymatically degraded. When amassed to sufficient concentrations, A2E can mediate detergent-like effects on cellular membranes (8, 9), alter lysosomal function (10, 11), and release proapoptotic proteins from …