Prevention of Photoreceptor Cell Loss in a Cln6nclf Mouse Model of Batten Disease Requires CLN6 Gene Transfer to Bipolar Cells
Prevention of Photoreceptor Cell Loss in a Cln6nclf Mouse Model of Batten Disease Requires CLN6 Gene Transfer to Bipolar Cells
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DOI：
10.1016/j.ymthe.2018.02.027
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发表时间：
2018-05-02
影响因子：
12.4
通讯作者：
Ali, Robin R.
中科院分区：
文献类型：
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作者：
Holthaus, Sophia-Martha Kleine;Ribeiro, Joana;Ali, Robin R.
神经元蜡样质脂褐质沉积症（NCL）是一种以全身性神经变性和过早死亡为特征的遗传性溶酶体贮积症。视力丧失也是NCL的主要症状，严重影响患者的生活质量，但脑定向治疗无法有效靶向。在这里，我们着手探索眼部基因治疗的治疗潜力，以治疗由于跨膜蛋白CLN6缺乏而导致的NCL视力丧失。我们发现，尽管Cln6（nclf）小鼠主要表现为光感受器变性，但在光感受器中补充CLN6并没有益处。由于CLN6的水平在光感受器中低，但在双极细胞（仅在疾病晚期在Cln6缺陷小鼠中丢失的视网膜中间神经元）中高，我们探索了使用腺相关病毒（AAV）血清型7m8将CLN6递送至双极细胞的治疗效果。CLN6的双极细胞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。这项研究表明，在双极细胞中正常表达的基因的缺乏会导致光感受器的损失，这可以通过双极细胞定向治疗来预防。
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(nclf) 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.