Batten diseases (BDs) are a group of lysosomal storage disorders characterized by seizure, visual loss, and cognitive and motor deterioration. We discovered increased levels of globotriaosylceramide (Gb3) in cellular and murine models of CLN3 and CLN7 diseases and used fluorescent-conjugated bacterial toxins to label Gb3 to develop a cell-based high content imaging (HCI) screening assay for the repurposing of FDA-approved compounds able to reduce this accumulation within BD cells. We found that tamoxifen reduced the lysosomal accumulation of Gb3 in CLN3 and CLN7 cell models, including neuronal progenitor cells (NPCs) from CLN7 patient-derived induced pluripotent stem cells (iPSC). Here, tamoxifen exerts its action through a mechanism that involves activation of the transcription factor EB (TFEB), a master gene of lysosomal function and autophagy. In vivo administration of tamoxifen to the CLN7^Δex2 mouse model reduced the accumulation of Gb3 and SCMAS, decreased neuroinflammation, and improved motor coordination. These data strongly suggest that tamoxifen may be a suitable drug to treat some types of Batten disease.

中文翻译：

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他莫昔芬的再利用可改善 CLN3 和 CLN7 疾病表型

Batten 病 (BD) 是一组溶酶体贮积症，其特征为癫痫发作、视力丧失以及认知和运动恶化。我们发现 CLN3 和 CLN7 疾病的细胞和小鼠模型中三酰神经酰胺 (Gb3) 水平升高，并使用荧光缀合细菌毒素来标记 Gb3，以开发基于细胞的高内涵成像 (HCI) 筛选测定法，以重新利用 FDA 批准的药物化合物能够减少 BD 细胞内的这种积累。我们发现他莫昔芬减少了 CLN3 和 CLN7 细胞模型中 Gb3 的溶酶体积累，包括来自 CLN7 患者来源的诱导多能干细胞 (iPSC) 的神经元祖细胞 (NPC)。在这里，他莫昔芬通过一种涉及转录因子 EB (TFEB) 激活的机制发挥其作用，转录因子 EB (TFEB) 是溶酶体功能和自噬的主基因。对 CLN7 ^{Δex2小鼠模型}体内给予他莫昔芬可减少 Gb3 和 SCMAS 的积累，减少神经炎症，并改善运动协调性。这些数据强烈表明他莫昔芬可能是治疗某些类型巴顿病的合适药物。