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Mutations in the retinitis pigmentosa GTPase regulator ( RPGR ) gene account for &gt;70% of X-linked retinitis pigmentosa (XLRP) and 15–20% of all inherited retinal degeneration. Gene replacement therapy for  RPGR -XLRP was hampered by the relatively slow disease progression in mouse models and by difficulties in cloning the full-length  RPGR-ORF15  cDNA that includes a purine-rich 3′-coding region; however, its effectiveness has recently been demonstrated in four dogs with  RPGR  mutations. To advance the therapy to clinical stage, we generated new stable vectors in AAV8 or AAV9 carrying mouse and human full-length  RPGR-ORF15 -coding sequence and conducted a comprehensive long-term dose-efficacy study in  Rpgr -knockout mice. After validating their ability to produce full-length proteins that localize to photoreceptor connecting cilia, we evaluated various vector doses in mice during a 2-year study. We demonstrate that eyes treated with a single injection of mouse or human  RPGR-ORF15  vector at an optimal dose maintained the expression of RPGR - ORF15 throughout the study duration and exhibited higher electroretinogram amplitude, thicker photoreceptor layer and better targeting of opsins to outer segments compared with sham-treated eyes. Furthermore, mice that received treatment at an advanced age also showed remarkable preservation of retinal structure and function. Retinal toxicity was observed at high vector doses, highlighting the importance of careful dose optimization in future clinical experiments. Our long-term dose-efficacy study should facilitate the design of human trials with human  RPGR-ORF15  vector as a clinical candidate.

A long-term efficacy study of gene replacement therapy for RPGR -associated retinal degeneration