Familial dysautonomia (FD) is a currently untreatable, neurodegenerative disease caused by a splicing mutation (c.2204+6T>C) that causes skipping of exon 20 of the elongator complex protein 1 () pre-mRNA. Here, we used adeno-associated virus serotype 9 (AAV9-U1-FD) to deliver an exon-specific U1 () small nuclear RNA, designed to cause inclusion of exon 20 only in those cells expressing the target pre-mRNA, in a phenotypic mouse model of FD. Postnatal systemic and intracerebral ventricular treatment in these mice increased the inclusion of exon 20. This also augmented the production of functional protein in several tissues including brain, dorsal root, and trigeminal ganglia. Crucially, the treatment rescued most of the FD mouse mortality before one month of age (89% vs 52%). There were notable improvements in ataxic gait as well as renal (serum creatinine) and cardiac (ejection fraction) functions. RNA-seq analyses of dorsal root ganglia from treated mice and human cells overexpressing FD-ExSpeU1 revealed only minimal global changes in gene expression and splicing. Overall then, our data prove that AAV9-U1-FD is highly specific and will likely be a safe and effective therapeutic strategy for this debilitating disease.

中文翻译：

---

通过 AAV9 外显子特异性 U1 snRNA 拯救家族性自主神经功能障碍小鼠模型


家族性自主神经功能障碍 (FD) 是一种目前无法治疗的神经退行性疾病，由剪接突变 (c.2204+6T>C) 引起，该突变导致延伸复合物蛋白 1 () 前 mRNA 的外显子 20 跳跃。在这里，我们使用腺相关病毒血清型 9 (AAV9-U1-FD) 传递外显子特异性 U1 () 小核 RNA，旨在仅在表达目标前 mRNA 的细胞中包含外显子 20， FD表型小鼠模型。这些小鼠出生后全身和脑室内治疗增加了外显子 20 的包含。这也增加了包括大脑、背根和三叉神经节在内的多个组织中功能蛋白的产生。至关重要的是，该治疗挽救了 1 个月龄前 FD 小鼠的大部分死亡率（89% vs 52%）。共济失调步态以及肾（血清肌酐）和心脏（射血分数）功能有显着改善。对过表达 FD-ExSpeU1 的治疗小鼠和人类细胞的背根神经节进行 RNA-seq 分析，结果显示基因表达和剪接的整体变化极小。总的来说，我们的数据证明 AAV9-U1-FD 具有高度特异性，并且可能成为这种使人衰弱的疾病的安全有效的治疗策略。