Department of Genetics, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK; MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK.
Department of Genetics, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
Mol Ther. 2018 May 2;26(5):1343-1353. doi: 10.1016/j.ymthe.2018.02.027. Epub 2018 Mar 2.
The neuronal ceroid lipofuscinoses (NCLs) are inherited lysosomal storage disorders characterized by general neurodegeneration and premature death. Sight loss is also a major symptom in NCLs, severely affecting the quality of life of patients, but it is not targeted effectively by brain-directed therapies. Here we set out to explore the therapeutic potential of an ocular gene therapy to treat sight loss in NCL due to a deficiency in the transmembrane protein CLN6. We found that, although Cln6 mice presented mainly with photoreceptor degeneration, supplementation of CLN6 in photoreceptors was not beneficial. Because the level of CLN6 is low in photoreceptors but high in bipolar cells (retinal interneurons that are only lost in Cln6-deficient mice at late disease stages), we explored the therapeutic effects of delivering CLN6 to bipolar cells using adeno-associated virus (AAV) serotype 7m8. Bipolar cell-specific expression of CLN6 slowed significantly the loss of photoreceptor function and photoreceptor cells. This study shows that the deficiency of a gene normally expressed in bipolar cells can cause the loss of photoreceptors and that this can be prevented by bipolar cell-directed treatment.
神经元蜡样脂褐质沉积症（NCLs）是一种遗传性溶酶体贮积病，其特征为广泛的神经退行性变和过早死亡。视力丧失也是 NCL 的主要症状，严重影响患者的生活质量，但目前尚无针对该症状的脑部靶向治疗方法。在这里，我们着手探索眼部基因治疗在治疗因跨膜蛋白 CLN6 缺乏引起的 NCL 视力丧失方面的治疗潜力。我们发现，尽管 Cln6 小鼠主要表现为光感受器变性，但补充 CLN6 对光感受器并无益处。由于 CLN6 在光感受器中的水平较低，但在双极细胞（视网膜中间神经元，仅在 Cln6 缺陷型小鼠的疾病晚期丢失）中水平较高，我们使用腺相关病毒（AAV）血清型 7m8 探索了向双极细胞传递 CLN6 的治疗效果。CLN6 在双极细胞中的特异性表达显著减缓了光感受器功能和光感受器细胞的丧失。本研究表明，通常在双极细胞中表达的基因的缺乏会导致光感受器的丧失，而这种丧失可以通过双极细胞靶向治疗来预防。
