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Halting progressive neurodegeneration in advanced retinitis pigmentosa
Susanne F. Koch, … , Chyuan-Sheng Lin, Stephen H. Tsang
Susanne F. Koch, … , Chyuan-Sheng Lin, Stephen H. Tsang
Published August 24, 2015
Citation Information: J Clin Invest. 2015;125(9):3704-3713. https://doi.org/10.1172/JCI82462.
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Research Article Neuroscience Article has an altmetric score of 17

Halting progressive neurodegeneration in advanced retinitis pigmentosa

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Abstract

Hereditary retinal degenerative diseases, such as retinitis pigmentosa (RP), are characterized by the progressive loss of rod photoreceptors followed by loss of cones. While retinal gene therapy clinical trials demonstrated temporary improvement in visual function, this approach has yet to achieve sustained functional and anatomical rescue after disease onset in patients. The lack of sustained benefit could be due to insufficient transduction efficiency of viral vectors (“too little”) and/or because the disease is too advanced (“too late”) at the time therapy is initiated. Here, we tested the latter hypothesis and developed a mouse RP model that permits restoration of the mutant gene in all diseased photoreceptor cells, thereby ensuring sufficient transduction efficiency. We then treated mice at early, mid, or late disease stages. At all 3 time points, degeneration was halted and function was rescued for at least 1 year. Not only do our results demonstrate that gene therapy effectively preserves function after the onset of degeneration, our study also demonstrates that there is a broad therapeutic time window. Moreover, these results suggest that RP patients are treatable, despite most being diagnosed after substantial photoreceptor loss, and that gene therapy research must focus on improving transduction efficiency to maximize clinical impact.

Authors

Susanne F. Koch, Yi-Ting Tsai, Jimmy K. Duong, Wen-Hsuan Wu, Chun-Wei Hsu, Wei-Pu Wu, Luis Bonet-Ponce, Chyuan-Sheng Lin, Stephen H. Tsang

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Figure 3

Preservation of retinal function after gene therapy administered at early, mid, and late disease stages.

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Preservation of retinal function after gene therapy administered at earl...
WT, mutant, and treated mice were measured at week 18. (A) Representative ERG responses for rods, mixed rods and cones, and cones from WT (black, WT), mutant (red, Mut), and treated mice. The treated mice were tamoxifen injected at 2 weeks (dark blue, T2), 4 weeks (green, T4), and 8 weeks (light blue, T8) of age. (B–E) Statistical analysis of ERG amplitudes for the scotopic rod-specific b-wave (B), the photopic cone-specific b-wave (C), the mixed rod-cone–specific a-wave (D), and the mixed rod-cone–specific b-wave (E). Gray dots represent individual mice (for each mouse, the 2 eyes were averaged; n values are shown below each group), and horizontal lines represent the group means. A linear regression model was fit to compare groups. *P < 0.05, **P < 0.01, and ***P < 0.001 for significant differences between treated and untreated mutant groups using linear regression model.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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