The neuronal ceroid lipofuscinoses (NCLs), often referred to as Batten disease, are inherited lysosomal storage disorders that represent the most common neurodegeneration during childhood. Symptoms include seizures, vision loss, motor and cognitive decline, and premature death. The development of brain-directed treatments for NCLs has made noteworthy progress in recent years. Clinical trials are currently ongoing or planned for different forms of the disease. Despite these promising advances, it is unlikely that therapeutic interventions targeting the brain will prevent loss of vision in patients as retinal cells remain untreated and will continue to degenerate. Here, we demonstrate that Cln3^Δex7/8 mice, a mouse model of CLN3 Batten disease with juvenile onset, suffer from a decline in inner retinal function resulting from the death of rod bipolar cells, interneurons vital for signal transmission from photoreceptors to ganglion cells in the retina. We also show that this ocular phenotype can be treated by adeno-associated virus (AAV)-mediated expression of CLN3 in cells of the inner retina, leading to significant survival of bipolar cells and preserved retinal function. In contrast, the treatment of photoreceptors, which are lost in patients at late disease stages, was not therapeutic in Cln3^Δex7/8 mice, underlining the notion that CLN3 disease is primarily a disease of the inner retina with secondary changes in the outer retina. These data indicate that bipolar cells play a central role in this disease and identify this cell type as an important target for ocular AAV-based gene therapies for CLN3 disease.

中文翻译：

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针对内层视网膜的基因治疗可挽救 CLN3 Batten 病小鼠模型的视网膜表型。

神经元蜡样脂褐质沉积症 (NCL)，通常称为 Batten 病，是一种遗传性溶酶体贮积症，是儿童时期最常见的神经变性病。症状包括癫痫发作、视力丧失、运动和认知能力下降以及过早死亡。近年来，NCL 的脑导向治疗取得了显着进展。目前正在进行或计划针对不同形式的疾病进行临床试验。尽管取得了这些有希望的进展，但由于视网膜细胞仍未得到治疗并将继续退化，因此针对大脑的治疗干预不太可能防止患者视力丧失。在这里，我们证明了Cln3 ^{Δ ex7/8}小鼠是幼年发病的 CLN3 Batten 病小鼠模型，由于杆状双极细胞死亡导致内部视网膜功能下降，中间神经元对于从光感受器到视网膜神经节细胞的信号传输至关重要。我们还表明，这种眼表型可以通过腺相关病毒 (AAV) 介导的CLN3在视网膜内细胞中的表达来治疗，从而导致双极细胞显着存活并保留视网膜功能。相比之下，在疾病晚期患者中丢失的光感受器的治疗在Cln3 ^{Δ ex7/8中没有治疗作用}小鼠，强调 CLN3 疾病主要是一种内层视网膜疾病，外层视网膜发生继发性变化。这些数据表明双极细胞在这种疾病中起着核心作用，并将这种细胞类型确定为基于 AAV 的眼部基因治疗 CLN3 疾病的重要靶标。