June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Gene therapy refutes non-autonomous rod cell death in a preclinical model of retinitis pigmentosa
Author Affiliations & Notes
  • Susanne Friederike Koch
    Ophthalmology, Columbia University, New York, New York, United States
  • Jimmy Duong
    Biostatistics, Columbia University, New York, New York, United States
  • Chun Wei Hsu
    Ophthalmology, Columbia University, New York, New York, United States
  • Yi-Ting Tsai
    Ophthalmology, Columbia University, New York, New York, United States
  • Chyuan-Sheng Lin
    Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, United States
  • Stephen Tsang
    Ophthalmology, Columbia University, New York, New York, United States
    Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, United States
  • Footnotes
    Commercial Relationships   Susanne Koch, None; Jimmy Duong, None; Chun Wei Hsu, None; Yi-Ting Tsai, None; Chyuan-Sheng Lin, None; Stephen Tsang, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 1574. doi:
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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)

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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.

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