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.

Fundus autofluorescence, spectral‐domain optical coherence tomography, and histology correlations in a Stargardt disease mouse model

“…This was clearly evidenced by an enhanced NIR‐AF in the melanosomes in the subretinal pigmented cells of blue light‐exposed Abca4 −/− mice. Likewise, the increase in melanin‐dependent NIR‐AF was demonstrated in most ABCA4‐STGD1 patients . These findings together indicate that photo‐oxidation linked to the changes in fluorescence properties of pigment granules (melanin, lipofuscin, and melanolipofuscin), is a common mechanism of the STGD1 phenotype and blue light damage in Abca4 −/− mice.…”

“…Likewise, the increase in melanin-dependent NIR-AF was demonstrated in most ABCA4-STGD1 patients. 70 These findings together indicate that photo-oxidation linked to the changes in fluorescence properties of pigment granules (melanin, lipofuscin, and melanolipofuscin), is a common mechanism of the STGD1 phenotype and blue light damage in Abca4 −/− mice. Loss of the RPE cells in the blue-light exposed mice was consistent with the reduction in the level of quantified bisretinoids by HPLC.…”

Scotopic Microperimetric Assessment of Rod Function in Stargardt Disease (SMART) Study: Design and Baseline Characteristics (Report No. 1)

“…Several STGD1 treatment approaches including pharmacological, gene augmentation and stem cell-therapy are in early clinical phases, although there are currently no FDA-approved therapies [5,6]. The success of clinical trials evaluating efficacy is largely dependent on sensitive and reproducible outcome measures.…”

“…Recent clinical studies have shown that in AMD the sensitivity of the rods decreases more rapidly than the sensitivity of the cones [21]. Although AMD and STGD1 are two different pathophysiological entities, they may share some common pathogenic features such as the photo-oxidative processes initiated by retinal pigment epithelium bisretinoids which could explain suggested links to light exposure in both STGD1 and AMD [6]. Hence, testing scotopic visual function may be indeed a promising additional outcome measure that may start to progress at a different stage of Data are presented as mean ± standard deviation (range).…”

“…Although there are at present no approved treatments, several therapeutic options are in preclinical or early clinical phases [3,5,6]. The Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) studies were launched to characterize the natural history of disease progression using a variety of structural and functional measures, including fundus autofluorescence (FAF; primary endpoint), spectral-domain optical coherence tomography (SD-OCT, using a Heidelberg Engineering [Heidelberg, Germany] device, respectively) and mesopic microperimetry (MP-1; Nidek Technologies, Padova, Italy).…”