Retinal degeneration is a common clinical feature of ciliopathies, a group of genetic diseases linked to ciliary dysfunction, and gene therapy is an attractive treatment option to prevent vision loss. Although the efficacy of retinal gene therapy is well established by multiple proof-of-concept preclinical studies, its long-term effect, particularly when treatments are given at advanced disease stages, is controversial. Incomplete treatment and intrinsic variability of gene delivery methods may contribute to the variable outcomes. Here, we used a genetic rescue approach to ‘optimally’ treat retinal degeneration at various disease stages and examined the long-term efficacy of gene therapy in a mouse model of ciliopathy. We used a Bardet–Biedl syndrome type 17 (BBS17) mouse model, in which the gene-trap that suppresses Bbs17 (also known as Lztfl1) expression can be removed by tamoxifen administration, restoring normal gene expression systemically. Our data indicate that therapeutic effects of retinal gene therapy decrease gradually as treatments are given at later stages. These results suggest the presence of limited time window for successful gene therapy in certain retinal degenerations. Our study also implies that the long-term efficacy of retinal gene therapy may depend on not only the timing of treatment but also other factors such as the function of mutated genes and residual activities of mutant alleles.

中文翻译：

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纤毛病临床前模型中视网膜基因治疗的有限时间窗口。

视网膜变性是纤毛病的常见临床特征，这是一组与纤毛功能障碍相关的遗传疾病，基因治疗是预防视力丧失的一种有吸引力的治疗选择。尽管多个概念验证临床前研究已经充分证实了视网膜基因治疗的疗效，但其长期效果，尤其是在疾病晚期阶段进行治疗时，仍存在争议。基因递送方法的不完全治疗和内在可变性可能导致可变结果。在这里，我们使用基因拯救方法“最佳”治疗不同疾病阶段的视网膜变性，并检查基因治疗在纤毛病小鼠模型中的长期疗效。我们使用了 Bardet-Biedl 综合征 17 型 (BBS17) 小鼠模型，其中抑制Bbs17的基因陷阱（也称为Lztfl1）表达可以通过他莫昔芬给药去除，系统地恢复正常的基因表达。我们的数据表明，随着治疗的后期给予，视网膜基因治疗的治疗效果逐渐下降。这些结果表明在某些视网膜变性中成功进行基因治疗的时间窗口有限。我们的研究还暗示，视网膜基因治疗的长期疗效可能不仅取决于治疗时机，还取决于其他因素，例如突变基因的功能和突变等位基因的残留活性。