| Summary: | Stargardt disease is caused by mutations in the ABCA4 gene and is probably the commonest inherited cause for retinal degeneration in youth with progressive visual deterioration. The Abca4-/- mouse is an animal model mimicking certain aspects of the human disease, including an accumulation of autofluorescent lipofuscin in the retinal pigment epithelium (RPE). The model is therefore ideally suited for preclinical investigation of novel treatment approaches for Stargardt disease. Imaging of lipofuscin- and melanin-related fundus autofluorescence (AF) was optimized in mice, which subsequently allowed investigating the mouse ocular phenotype in vivo. The Abca4-/- mouse showed an age-related increase in lipofuscin- and melanin-related AF intensity, correlating to an increase of ex vivo assessed bis-retinoid-fluorophores and formation of melanolipofuscin granules, respectively. Retinal function remained largely unaffected by those changes within the RPE. Abca4-/- mice were fed with C20-deuterized vitamin A (C20dVitA) which had been shown to inhibit lipofuscin-formation in the RPE. The diet markedly reduced lipofuscin- and melanin-related AF intensity to levels measured in wild type animals on a normal diet. This treatment did not affect retinal function. The possibility of performing similar fundus AF measurements in humans may allow fast translation of this therapy into clinical trials. The only causative treatment approach for Stargardt disease will be gene replacement therapy. Investigation of various mutant adeno-associated viruses (AAVs) as vector for delivering ABCA4 revealed that photoreceptors in Abca4-/- mice were more difficult to transduce than photoreceptors in wild type mice. This indicates an influence of the diseased retina on gene delivery. Thus, very efficient viruses might be needed to achieve relevant ABCA4 expression in the retina of patients with Stargardt disease. In summary, application of a clinically relevant imaging method allows to assess the ocular phenotype of the mouse model for Stargardt disease and to investigate novel treatment strategies.
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