Huntington's disease (HD) is a neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene that results in the production of neurotoxic mutant HTT (mHTT) protein. Suppressing HTT production with antisense oligonucleotides (ASOs) is a promising treatment strategy for HD; however, the difficulty of delivering ASOs to deep brain structures is a major barrier for its clinical application. The glymphatic system of astrocytes involving aquaporin 4 (AQP‐4) controls the entry of macromolecules from the cerebrospinal fluid into the brain. Mesenchymal stem cells (MSCs) target astrocytes to inhibit neuroinflammation. Here we examined the glymphatic distribution of ASO in the brain and the therapeutic potential of combining intravenously injection of mesenchymal stem cells (IV‐MSC) and ASOs for the treatment of HD. Our results show that Cy3‐labeled ASOs entered the brain parenchyma via the perivascular space following cisternal injection, but the brain distribution was significantly lower in AQP‐4−/− as compared with wild‐type mice. Downregulation of the AQP‐4 M23 isoform was accompanied by decreased brain levels of ASOs in BACHD mice as well as an increase in astrogliosis and phosphorylation of nuclear factor κB (NF‐κB) p65. IV‐MSC treatment restored AQP‐4 M23 expression, attenuated astrogliosis, and decreased NF‐κB p65 phosphorylation; it also increased the brain distribution of ASOs and enhanced the suppression of mHTT in BACHD mice. These results suggest that modulating glymphatic activity using IV‐MSC is a novel strategy for improving the potency of ASO in the treatment of HD.

中文翻译：

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间充质干细胞减轻 AQP-4 依赖性淋巴系统功能障碍并改善 BACHD 小鼠反义寡核苷酸的脑分布

亨廷顿病 (HD) 是一种神经退行性疾病，由亨廷顿 (HTT) 基因突变导致产生神经毒性突变 HTT (mHTT) 蛋白。用反义寡核苷酸 (ASO) 抑制 HTT 的产生是一种很有前景的 HD 治疗策略。然而，将 ASO 递送到大脑深部结构的困难是其临床应用的主要障碍。涉及水通道蛋白 4 (AQP-4) 的星形胶质细胞淋巴系统控制大分子从脑脊液进入大脑。间充质干细胞 (MSC) 靶向星形胶质细胞以抑制神经炎症。在这里，我们检查了 ASO 在大脑中的淋巴分布以及联合静脉注射间充质干细胞 (IV-MSC) 和 ASO 治疗 HD 的治疗潜力。我们的结果表明，Cy3 标记的 ASO 在脑池注射后通过血管周围空间进入脑实质，但与野生型小鼠相比，AQP-4-/- 中的脑分布显着降低。AQP-4 M23 亚型的下调伴随着 BACHD 小鼠脑中 ASOs 水平的降低以及星形胶质细胞增生和核因子 κB (NF-κB) p65 磷酸化的增加。IV-MSC 治疗恢复 AQP-4 M23 表达，减轻星形胶质细胞增生，并降低 NF-κB p65 磷酸化；它还增加了 ASO 的大脑分布并增强了对 BACHD 小鼠 mHTT 的抑制。这些结果表明，使用 IV-MSC 调节淋巴活动是一种提高 ASO 治疗 HD 效力的新策略。