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Peter Charbel Issa, Alun R Barnard, Ilyas Washington, Robert E MacLaren; C20-D3-Vitamin A (ALK-001) rescues the phenotype of an Abca4−/− mouse model of Stargardt disease. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5015.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the effect of C20-D3-Vitamin A (ALK-001) on the phenotype of the Abca4−/− mouse
Abca4−/− mice treated with ALK-001 for various amounts of time (3, 6, 7.5 and 9 months) were compared to untreated Abca4−/− mice and wild type (WT) controls reared on chow containing normal amounts of vitamin A. Quantitative fundus autofluorescence (AF) imaging and electroretinography (ERG) were assessed in vivo (n=10 per group) and assessment of bisretinoid (A2E) accumulation was then performed postmortem
In all Abca4−/− mice that received ALK-001, lipofuscin-related fundus AF levels were significantly lower than in untreated Abca4−/− controls, in which AF levels were about twice those of WT controls at 9 months.The longer animals had stayed on ALK-001, the lower their AF signals. The most significant effect was observed in Abca4−/− mice maintained on ALK-001 for 9 months, with AF signals similar to those of untreated WT controls. When animals were crossed over from ALK-001 to normal chow, AF signals increased steeply. Absence of diet-related changes on scotopic and photopic ERG recordings between the same groups of 9 month-old animals indicated that ALK-001 was safe to the retina. Post-mortem analyses of eye cups revealed an about 8-fold increase of A2E in 9-month old Abca4−/− mice compared to WT controls, while treatment with ALK-001 from birth reduced bisretinoid concentration in eyes of Abca4−/− mice down to the levels measured in WT controls.
These experiments confirm that an increase in the concentration of ocular A2E levels is paralleled by an increase in fundus AF intensity, and that treatment effects of C20-D3-vitamin A (ALK-001) in mice can be monitored with measurement of A2E and AF intensity. Finally, the results demonstrate that ALK-001 can be administered safely in mice and rescues the phenotype of a mouse model of Stargardt disease by reducing the rate of formation of autofluorescent materials in the eyes, without negatively affecting the ERG recordings.
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