Abstract
Purpose :
P23H-1 transgenic rats exhibit retinal degeneration of the photoreceptors/outer nuclear layer (PR/ONL) due to insertion of a mutated mouse rhodopsin gene and are used as a model for mechanistic/efficacy studies for autosomal dominant retinitis pigmentosa. The reported rate of ONL thinning is ∼60% by post partum day 30 (pp30) and ∼80% by pp60. The objective was to determine if low light housing conditions during the 1st month pp, when ocular structures are still under development, would delay the initial rate of degeneration, preserving the ONL cell layer enough to support a dose response neuroprotection efficacy regimen commencing ∼ pp21-pp30.
Methods :
P23H-1 pups were housed under a 12hr light/dark cycle with a maximum of 20 lux room light during the light cycle until pp30, after which standard room light intensity of 200 lux was used. PR/ONL thickness was measured by SD-OCT and ERG recorded at approximately pp30, 45 and 60 with a stimulus intensity (SI) of 2.5 cd.s/m2. Microscopic evaluation of H&E-stained eye sections was done at pp60.
Results :
The rates of ONL/PR thinning were 18% and 23% between pp30 and pp45, and pp45 and pp60, respectively. Total reduction was 37% over 4 weeks. Previously reported ONL thinning ranged from ∼50% (LaVail et al 2018) to ∼21% (Ohran et al 2015) for the same 4 wk time period. Mean ONL thickness was ∼40 µm at pp30 with the dim light protocol and 20 to 29 µm in standard room light for LaVail and Ohran, respectively. Reduction in scotopic ERG b-wave amplitude was 18% over 4 weeks from pp30 - pp60 vs ∼48% reported by LaVail (2.4 cd.s/m2 SI) and ∼25% reported by Ohran (12 cd.s/m2 SI), Microscopic evaluation showed 5-7 ONL cell layers on pp60 (10-12 normal for WT), compared to 2-4 layers reported by LaVail (Ohran not reported).
Conclusions :
Overall the rate of physical degeneration appeared to be slowed under low light for the first 30 days pp given the absolute ONL thickness at that point and the number of ONL cell layers remaining by pp60 vs previously reported values. The rate of PR/ONL thinning in the 1st 60 days pp appeared to be sufficient to detect a dose response, but the ERG changes compared to the literature did not support an obvious advantage in the short term at least, possibly influenced by the differences in breeding stock, anesthetic regimens and/or in light exposure from birth to 60 days pp between these 3 references.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.