Abstract
Purpose :
A typical feature of retinitis pigmentosa (RP) is the initial loss of photoreceptors, followed by remodeling of the inner retina and blood vessels. How these changes may ultimately limit therapy outcome remains unknown. In this study we investigate if gene therapy at different RP disease stages can halt or even reverse retinal remodeling.
Methods :
We use a novel genetically engineered RP mouse model (Pde6bSTOP/STOP, Pde6g::CreERT2/+), which carries a floxed STOP cassette on both alleles and expresses a rod specific tamoxifen inducible Cre. Mice were treated at 4, 12, 16 and 24 week of age by tamoxifen-induced Cre activation; at the time point of treatment the outer nuclear layer thickness had decreased by 37%, 67%, 82% and 88%, respectively (relative to the 40 weeks old wild-type). The remodeling and rescue of vision were evaluated by ERG recordings, water maze test and immunohistochemistry. The retinal vasculature was analyzed by immunohistochemistry and trypsin digests stained with H&E.
Results :
In our RP mouse model, we observed progressive loss of rod bipolar processes, delocalized rod biplolar cell bodies, and dramatic reductions of horizontal cell neurites. Remodeling of inner retinal cells is halted and the function rescued after treatment at 16 weeks or earlier, but not by treatment at 24 weeks. The successful restoration of vision was preserved at least until age of 40 weeks. The retinal degeneration in our RP model is accompanied by blood vessel remodeling, which can be quantified as the reduced area of the vasculature and increased number of acellular capillaries. Mice treated at 16 weeks of age or earlier had significantly less acellular capillaries at 40 weeks of age than the untreated RP mice.
Conclusions :
The results show that inner retinal remodeling can be halted in the long term after treatment at 16 weeks of age or earlier; however, inner retinal plasticity remains limited. In addition, we observed a positive effect of our treatment on the retinal vasculature remodeling.
This is a 2021 ARVO Annual Meeting abstract.