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Susanne Friederike Koch, Jimmy Duong, Chun Wei Hsu, Yi-Ting Tsai, Chyuan-Sheng Lin, Stephen Tsang; Gene therapy refutes non-autonomous rod cell death in a preclinical model of retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1574.
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© ARVO (1962-2015); The Authors (2016-present)
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.
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.
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).
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.
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