Therapeutics based on short interfering RNAs (siRNAs) delivered to hepatocytes have been approved, but new delivery solutions are needed to target additional organs. Here we show that conjugation of 2′-O-hexadecyl (C16) to siRNAs enables safe, potent and durable silencing in the central nervous system (CNS), eye and lung in rodents and non-human primates with broad cell type specificity. We show that intrathecally or intracerebroventricularly delivered C16-siRNAs were active across CNS regions and cell types, with sustained RNA interference (RNAi) activity for at least 3 months. Similarly, intravitreal administration to the eye or intranasal administration to the lung resulted in a potent and durable knockdown. The preclinical efficacy of an siRNA targeting the amyloid precursor protein was evaluated through intracerebroventricular dosing in a mouse model of Alzheimer’s disease, resulting in amelioration of physiological and behavioral deficits. Altogether, C16 conjugation of siRNAs has the potential for safe therapeutic silencing of target genes outside the liver with infrequent dosing.

基于递送至肝细胞的短干扰 RNA (siRNA) 的疗法已获批准，但需要新的递送解决方案来靶向其他器官。在这里，我们展示了 2'- O的缀合siRNA 的十六烷基 (C16) 可在具有广泛细胞类型特异性的啮齿动物和非人类灵长类动物的中枢神经系统 (CNS)、眼睛和肺中实现安全、有效和持久的沉默。我们表明，鞘内或脑室内递送的 C16-siRNA 在 CNS 区域和细胞类型中都很活跃，具有持续的 RNA 干扰 (RNAi) 活性至少 3 个月。类似地，对眼睛进行玻璃体内给药或对肺进行鼻内给药会导致有效且持久的抑制作用。靶向淀粉样蛋白前体蛋白的 siRNA 的临床前疗效通过在阿尔茨海默病小鼠模型中的脑室内给药进行评估，从而改善生理和行为缺陷。共，