Abstract
Purpose:
To investigate the effect of C20-D3-Vitamin A (ALK-001) on the phenotype of the Abca4−/− mouse
Methods:
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
Results:
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.
Conclusions:
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.
Keywords: 696 retinal degenerations: hereditary •
551 imaging/image analysis: non-clinical