Retinitis pigmentosa (RP) is hereditary retinal degenerative disease that is characterized by progressive loss of photoreceptor function. In human trials, gene therapy has been shown to improve vision; however, this benefit has not been sustainable. It is not clear if the lack of long-term benefit is due to the advanced stage of the disease at the time of therapy or due to inefficient delivery of the functional gene. In this episode, Stephen Chang and Susanne Koch discuss the development of a murine RP model that allows induction of the corrected gene at various stages of disease. The results of their study indicate that gene therapy can treat RP even at advanced stages and that future studies should focus on improving gene delivery.
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.
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