Abstract
Purpose :
In gene therapy-treated retinas, the therapeutic gene transduces only a fraction of the target diseased rods – thereby creating a mosaic of untreated and treated mutant rods, as well as cones. In this study, we tested whether treated rods are negatively impacted by the surrounding dying untreated rods.
Methods :
We created two novel retinitis pigmentosa (RP) mouse models in which mutant rod-specific cGMP phosphodieserase 6b (PDE6B) can be restored to WT in spatially or numerically controlled rods. Then we analyzed the survival of treated rods at 2.5, 5, 9 and 12 months of age. A linear regression model was used for statistical analysis.
Results :
In one model, treated and untreated rods were spatially segregated. In untreated areas, the photoreceptors dramatically degenerated, and this was reflected by a significant decrease in outer nuclear layer (ONL) thickness over time (p < 0.003). In treated areas, ONL thickness did not significantly change (p = 0.5). In the second model, the ratio of treated and untreated rods was controlled and the two cell types intermixed. In this model, we demonstrated that when 30%, 50% or 70% of photoreceptors were rescued (ie, low-, medium- and high-efficiency gene therapy, respectively), 8 months later, the percentage of surviving photoreceptors was statistically unchanged (p = 0.6, 0.9 and 0.3, respectively).
Conclusions :
We demonstrated that untreated rods did not impact the survival of treated rods. Our study suggests that monogenic gene therapy can achieve long-term efficacy in RP retinas, even in an overwhelmingly mutant environment.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.