Mata, Nathan L; Weng, Stephanie; Michaelides, Michel; Charbel Issa, Peter; Quinodoz, Mathieu; Rivolta, Carlo; Scholl, Hendrik PN; (2025) Bisretinoids as a Source of Early Photoreceptor Pathology in Stargardt Disease. Ophthalmic Research 10.1159/000549368. (In press).

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Abstract

BACKGROUND: Stargardt disease (STGD1) due to bi-allelic mutations in the ABCA4 gene is the most frequent single-gene retinal disease with a genetic prevalence of about 1 in 7,000. Pathology in STGD1 is due to dysfunction of a retina-specific vitamin A transporter which causes accumulation of cytotoxic vitamin A byproducts known as bisretinoids. Bisretinoids produce a distinct autofluorescent emission within affected cells that is seen to precede atrophy of the retinal pigment epithelium (RPE), photoreceptor cell death, and vision loss. This sequence of pathogenesis, and the fact that formation and accumulation of bisretinoids begins within photoreceptors, suggests early pathology may occur within photoreceptor cells. Here, relevant literature is reviewed to explore the relationship between bisretinoids, fundus autofluorescence, and photoreceptor function/integrity in STGD1 with a focus on early-stage disease and potential biomarkers for clinical investigation. SUMMARY: Currently accepted primary endpoints in STGD1 clinical trials include quantification of areas where the autofluorescence signal is lacking due to the death of RPE and photoreceptor cells. Importantly, many patients with early-stage STGD1 cannot be monitored in this way as they present clinically prior to RPE or photoreceptor loss at a pre-atrophic stage and without significant visual impairment. Imaging analyses of patients with early-stage disease have shown increased fundus autofluorescence and compromised photoreceptor integrity and/or visual function deficits in the absence of atrophic retinal lesions. These findings implicate early accumulation of bisretinoid toxins within the retina as an underlying causative factor and provide an impetus to determine the relevance of these measures as surrogate endpoints or biomarkers for disease progression in STGD1 clinical trials. KEY MESSAGES: Early recognition and treatment of patients with STGD1 who have relatively healthy retinal tissue will likely yield a more favorable visual prognosis. Accordingly, there is a need to identify early disease initiators and progression patterns. The reviewed data support the hypothesis that bisretinoid accumulation within photoreceptors may be responsible for the observed early retinal pathology and vision loss. Clinical evaluation of therapeutics intended to reduce bisretinoid accumulation in early-stage STGD1 patients will likely provide a greater understanding of the role of bisretinoids in disease progression and potential for vision preservation.

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