英国阿里拉姆制药Vasant Jadhav、Martin A. Maier等研究人员合作发现，利用亲脂性结合物可将RNAi治疗剂扩展到肝外组织。2022年6月2日，《自然—生物技术》杂志在线发表了这项成果。

研究人员发现，将2′-O-十六烷基（C16）与短干扰RNA（siRNA）结合，可以在啮齿动物和非人灵长类动物的中枢神经系统（CNS）、眼睛和肺部进行安全、有效和持久的沉默，并具有广泛的细胞类型特异性。结果表明，肝内或脑室内给药的C16-siRNA在不同的中枢神经系统区域和细胞类型中都有活性，其持续的RNA干扰（RNAi）活性至少可达3个月。

同样，玻璃体内给药到眼睛或鼻腔内给药到肺部，也能达到有效和持久的敲除效果。在阿尔茨海默病的小鼠模型中，通过脑室内给药评估了针对淀粉样前体蛋白的siRNA的临床前疗效，结果是生理和行为缺陷得到了改善。总的来说，C16连接的siRNA有可能在肝脏外安全地治疗沉默目标基因，而且不用经常给药。

据悉，基于siRNA递送到肝细胞的治疗方法已经获得批准，但需要新的递送方案来靶向其他器官。

附：英文原文

Title: Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates

Author: 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

Issue&Volume: 2022-06-02

Abstract: 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 3months. 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.

DOI: 10.1038/s41587-022-01334-x

Source: https://www.nature.com/articles/s41587-022-01334-x