A mouse model of advanced Stargardt disease and its application in preclinical assessment of a new pharmacological therapy

Abstract

Stargardt disease (STGD1), known as the most prevalent form of inherited macular dystrophy, is related to ABCA4 mutations. The pigmented Abca4-/- mouse strain is considered to be a mouse model of the early phase of Stargardt disease, due to the absence of retinal degeneration. In this study, to induce retinal degeneration in pigmented Abca4-/- mice, these mice were illuminated with blue light. By comparing the in vivo assessments including ERG, fundus SW-AF, fundus NIR-AF and OCT from the mouse model to those from Stargardt patients, I demonstrated that this mouse model reflected the clinical manifestations of advanced Stargardt disease. The results indicated that acute blue light reduced the mean AF intensities of fundus SW-AF and NIR-AF. Additionally, it was indicated that RPE loss preceded the photoreceptor loss in the blue light-illuminated Abca4-/- mice. In albino Abca4-/- mice, NIR-AF was observed after blue light illumination. Lipofuscin and melanolipofuscin granules were found to contribute to NIR-AF, in the late-stage Stargardt patient and blue light-illuminated Abca4-/- mice. It suggested that Stargardt disease and blue light damage in Abca4-/- mice shared a common pathological process which changed the fluorescence properties of lipofuscin and melanin. In this mouse model, the correlation between in vivo and ex vivo assessments revealed histological characteristics of fundus AF abnormalities. The subretinal macrophages fully packed with pigment granules (lipofuscin, melanin, melanolipofuscin) were found as one of the sources of the fundus hyper SW-AF and NIR-AF. This mouse model, which has the phenotypes of advanced STGD1, is important to understand the histopathology of Stargardt disease. This model also could be used for preclinical study of therapy strategies for the advanced stage of Stargardt disease. Remofuscin®, a remover of lipofuscin, was applied in this mouse model. Single intravitreal injection of Remofuscin® removed lipofuscin from RPE cells thus suppressed blue light-induced retinal degeneration. Remofuscin® is a potential therapeutic drug for lipofuscin-related retinopathies.