Abstract
Purpose :
Effective treatment of chronic retinal degenerations will require a strategy that is well tolerated in elderly patients and safe; the use of FDA approved drugs may provide an accelerated pathway to development. We have previously demonstrated that the P2Y12 receptor antagonist ticagrelor (Brilinta) restored lysosomal acidity and reduced autofluorescence in compromised RPE cells from ABCA4-/- mice. Here we tested whether oral delivery of ticagrelor can actually preserve vision in ABCA4-/- mice.
Methods :
Albino ABCA4-/- mice were fed 0.1-0.15% ticagrelor in their chow for 1.5-7 months, with control mice using normal chow. As this mouse model shows minimal photoreceptor damage, a moderate light exposure regime of 4 hrs in 10,000 lux white light was used to enhance retinal degeneration. Retinal function was determined with electroretinogram (ERG) recordings. Photoreceptor survival was determined by evaluating outer nuclear layer (ONL) thickness with optical coherence tomography (OCT) and counting nuclei in the ONL using histological sections.
Results :
Addition of ticagrelor to chow was associated with protection of photoreceptors after light exposure. The a- and b-wave ERG recordings at intensities of 0.1 and 1.0 cd.s/m2 were significantly greater in the ticagrelor-treated mice. This difference in a- and b- wave performance was present 1, 7 and 14 days after exposure to light, implying a permanent protection. OCT measurements showed the thickness of the ONL was greater in mice treated with ticagrelor than in the untreated mice after light exposure. These OCT findings were supported by histological examination, with the number of surviving photoreceptor nuclei greater in mice treated with ticagrelor than control. Chronic treatment with ticagrelor appeared safe in mice exposed to normal light levels, as mice treated for 7 months showed no difference in thickness of the ONL or changes in the fundus appearance as compared to untreated controls.
Conclusions :
These observations identify inhibition of the P2Y12 receptor as a useful target in protecting photoreceptor function in retinal degeneration. Ticagrelor was previously shown to low lysosomal pH and increase degradation of lysosomal waste in these mice, suggesting protection is associated with lysosomal stabilization. As Brilinta is widely used in the aged population, these results may identify a useful target for treatment of age-related retinal degenerations.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.