Brown Kirk M, Nair Jayaprakash K, Janas Maja M, Anglero-Rodriguez Yesseinia I, Dang Lan T H, Peng Haiyan, Theile Christopher S, Castellanos-Rizaldos Elena, Brown Christopher, Foster Donald, Kurz Jeffrey, Allen Jeffrey, Maganti Rajanikanth, Li Jing, Matsuda Shigeo, Stricos Matthew, Chickering Tyler, Jung Michelle, Wassarman Kelly, Rollins Jeff, Woods Lauren, Kelin Alex, Guenther Dale C, Mobley Melissa W, Petrulis John, McDougall Robin, Racie Timothy, Bombardier Jessica, Cha Diana, Agarwal Saket, Johnson Lei, Jiang Yongfeng, Lentini Scott, Gilbert Jason, Nguyen Tuyen, Chigas Samantha, LeBlanc Sarah, Poreci Urjana, Kasper Anne, Rogers Arlin B, Chong Saeho, Davis Wendell, Sutherland Jessica E, Castoreno Adam, Milstein Stuart, Schlegel Mark K, Zlatev Ivan, Charisse Klaus, Keating Mark, Manoharan Muthiah, Fitzgerald Kevin, Wu Jing-Tao, Maier Martin A, Jadhav Vasant
Alnylam Pharmaceuticals, Cambridge, MA, USA.
Nat Biotechnol. 2022 Oct;40(10):1500-1508. doi: 10.1038/s41587-022-01334-x. Epub 2022 Jun 2.
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。在此我们表明，将2'-O-十六烷基（C16）与siRNA偶联能够在啮齿动物和非人类灵长类动物的中枢神经系统（CNS）、眼睛和肺部实现安全、有效且持久的基因沉默，具有广泛的细胞类型特异性。我们发现，经鞘内或脑室内递送的C16-siRNA在整个CNS区域和细胞类型中均有活性，RNA干扰（RNAi）活性持续至少3个月。同样，玻璃体内注射至眼睛或经鼻给药至肺部均导致有效且持久的基因敲低。通过在阿尔茨海默病小鼠模型中进行脑室内给药，评估了靶向淀粉样前体蛋白的siRNA的临床前疗效，结果生理和行为缺陷得到改善。总之，siRNA的C16偶联有潜力通过不频繁给药对肝脏以外的靶基因进行安全的治疗性沉默。
