RPE65 gene therapy slows cone loss in Rpe65-deficient dogs
RPE65 gene therapy slows cone loss in Rpe65-deficient dogs
复制标题
DOI：
10.1038/gt.2012.63
复制
发表时间：
2013-05-01
期刊：
影响因子：
5.1
通讯作者：
Ali, R. R.
中科院分区：
文献类型：
--
作者：
Mowat, F. M.;Breuwer, A. R.;Ali, R. R.
最近在Leber先天性黑蒙2型患者中进行的视网膜色素上皮基因（RPE 65）补充治疗的临床试验已经证明了视杆细胞和视锥细胞功能的改善，但治疗对感光细胞存活的影响可能需要几年时间才能显现出来。Rpe 65缺陷型犬是一种非常有用的临床前模型，用于测试治疗效果，因为犬的视网膜与人的视网膜高度相似。在这项研究中，我们评估了RPE 65基因治疗对感光细胞存活的影响，以预测患者治疗的潜在益处和局限性。我们检查了RPE 65基因治疗后RPE 65缺陷狗的视网膜，以评估视杆细胞和视锥细胞感光亚型的保存情况。我们发现基因治疗保留了视杆细胞和视锥细胞。虽然Rpe 65缺陷的狗视网膜中的杆的中度损失通过基因治疗减缓，但S-视锥细胞广泛损失，基因治疗可以防止这种损失，尽管仅在治疗区域内。虽然LM-视锥细胞并没有大量丢失，但视锥细胞视蛋白的错误定位表明它们受到了压力，并且这可以通过基因治疗部分逆转。我们的研究结果表明，基因治疗可能能够减缓锥细胞变性的患者，如果干预是足够早的，也可能是重要的，以保护中央功能，以治疗黄斑。
Recent clinical trials of retinal pigment epithelium gene (RPE65) supplementation therapy in Leber congenital amaurosis type 2 patients have demonstrated improvements in rod and cone function, but it may be some years before the effects of therapy on photoreceptor survival become apparent. The Rpe65-deficient dog is a very useful pre-clinical model in which to test efficacy of therapies, because the dog has a retina with a high degree of similarity to that of humans. In this study, we evaluated the effect of RPE65 gene therapy on photoreceptor survival in order to predict the potential benefit and limitations of therapy in patients. We examined the retinas of Rpe65-deficient dogs after RPE65 gene therapy to evaluate the preservation of rods and cone photoreceptor subtypes. We found that gene therapy preserves both rods and cones. While the moderate loss of rods in the Rpe65-deficient dog retina is slowed by gene therapy, S-cones are lost extensively and gene therapy can prevent that loss, although only within the treated area. Although LM-cones are not lost extensively, cone opsin mislocalization indicates that they are stressed, and this can be partially reversed by gene therapy. Our results suggest that gene therapy may be able to slow cone degeneration in patients if intervention is sufficiently early and also that it is probably important to treat the macula in order to preserve central function.