Towards Treatment of Stargardt Disease: Workshop Organized and Sponsored by the Foundation Fighting Blindness

Abstract

Accumulation of fluorescent metabolic byproducts of the visual (retinoid) cycle is associated with photoreceptor and retinal pigment epithelial cell death in both Stargardt disease and atrophic (nonneovascular) age-related macular degeneration (AMD). As a consequence of this observation, small molecular inhibitors of enzymes in the visual cycle were recently tested in clinical trials as a strategy to protect the retina and retinal pigment epithelium in patients with atrophic AMD. To address the clinical translational needs for therapies aimed at both diseases, a workshop organized by the Foundation Fighting Blindness was hosted by the Department of Pharmacology at Case Western Reserve University on February 17, 2017, at the Tinkham Veale University Center, Cleveland, OH, USA. Invited speakers highlighted recent advances in the understanding of the pathophysiology of Stargardt disease, in terms of its clinical characterization and the development of endpoints for clinical trials, and discussed the comparability of therapeutic strategies between atrophic age-related macular degeneration (AMD) and Stargardt disease. Investigators speculated that reducing the concentrations of visual cycle precursor substances and/or their byproducts may provide valid therapeutic options for the treatment of Stargardt disease. Here we review the workshop's presentations in the context of published literature to help shape the aims of ongoing research endeavors and aid the development of therapies for Stargardt disease.

Keywords: A2E, all-trans-retinal; ABCA4; Stargardt disease; age-related macular degeneration; geographic atrophy; lipofuscin.

Figure 1

Rod and cone photoreceptors and ABCA4 mechanism in OS disc membranes. In both rod and cone cells, the light-sensitive OS is attached to the inner segment (IS) by a connecting cilium (CC). Rhodopsin, the visual pigment in rod cells, comprises the protein opsin bound to the chromophore 11-cis-retinal, which is isomerized to all-trans-retinal upon photon absorption. Once released from opsin, all-trans-retinal then reacts with PE to form a Schiff base. ABCA4 then “flips” all-trans-retinal to the outer portion of the disc membrane to access the visual cycle.

Figure 2

The visual (retinoid) cycle in ABCA4 mediated disease. The retinoid cycle, supporting both rod and cone photoreceptor cells, displaying the enzymatic conversion of all-trans-retinal to 11-cis-retinal. Absorption of a photon of light (hv) by the visual pigment (11-cis-retinylidene-opsin) is isomerized to the active state of rhodopsin. Hydrolysis of the Schiff base linkage then releases free all-trans-retinal, which conjugates to PE within the disc membrane to form N-retinylidene-PE. Acting as an importer, ABCA4 hydrolyzes ATP by its cytoplasmic ATPase domains to flip a molecule of the N-retinylidene-PE Schiff base conjugate from the intradiscal space to the cytoplasm, where this conjugate is hydrolyzed and the all-trans-retinal is reduced to the nontoxic all-trans-retinol. The molecule is transported across the interphotoreceptor matrix by interphotoreceptor retinoid binding protein (IRBP) to the RPE where it is esterified by LRAT and subsequently isomerized by RPE65 to form the 11-cis-retinal molecule, which is able to bind opsin to form the visual chromophore after transport back to photoreceptors by IRBP. In the absence of functional ABCA4, all-trans-retinal will accumulate in OS membranes, which leads to the accumulation of bisretinoid and lipofuscin in both photoreceptors and the RPE, a hallmark of ABCA4 mediated disease, and ultimately cell death.