Abstract
Purpose :
In autosomal recessive Stargardt disease (STGD1) and dry age-related macular degeneration (AMD), excessive accumulation of lipofuscin is associated with retinal pigment epithelium (RPE) cell death, photoreceptor cell damage, and vision loss. A2E and iso-A2E are prominent fluorophores of ocular lipofuscin that mediate phototoxicity and degeneration. Previous work from our lab in vitro, in quail eyes, and in human donor eyes have indicated that macular carotenoids (MC) can attenuate bisretinoid formation and phototoxicity, but mouse studies have been hampered by poor carotenoid uptake due to their very active carotenoid cleavage enzyme, Bco2. In this study, we have crossed Bco2 KO “macular pigment mice” with a mouse model of STGD1.
Methods :
Abca4-/-/Bco2-/- and Abca4-/- mice on C57BL6/J background were fed with lutein, zeaxanthin, or a placebo chow (∼2.6 mg of carotenoid/mouse/day; DSM, Kaiseraugst, Switzerland; n=12/group) for 3 months, and their optokinetic response (OKR), electroretinography (ERG) and optical coherence tomography (OCT) were measured after 1-3 months of carotenoid supplementation. Mice were sacrificed after 3 months of supplementation, and their blood and tissues (eye, liver, and brain) were collected. A2E and iso-A2E levels from RPE/choroid and carotenoid levels from the retina were quantified by HPLC
Results :
Lutein and zeaxanthin supplemented Abca4-/-/Bco2-/- mice had 33-71% lower levels of RPE/choroid A2E and iso-A2E compared to control mice fed with placebo chow (p<0.05) and had improved visual performance. Carotenoid supplementation in Abca4-/- mice minimally raised retinal carotenoid levels and did not show much difference in bisretinoid levels or visual acuity compared to the control diet-fed group. There was a statistically significant inverse correlation between MC levels in the retina and A2E and iso-A2E levels in the RPE/choroid. Scotopic and photopic a and b-wave response and photoreceptor cell viability did not show any significant differences relative to WT mice of same age in either mouse line, irrespective of their supplementation status.
Conclusions :
Supplementation with MC effectively reduces bisretinoid formation and improves visual acuity in a mouse model of STGD1 genetically enhanced to accumulate carotenoids in the retina. These results provide further impetus to pursue oral carotenoids as therapeutic interventions for STGD1 and AMD.
This is a 2021 ARVO Annual Meeting abstract.