GalNAc-siRNA共轭物：引领RNAi治疗药物的传递途径

StephenW

GalNAc-siRNA Conjugates: Leading the Way for Delivery of RNAi Therapeutics
Springer Aaron D.
and Dowdy Steven F.
Published Online:1 Jun 2018https://doi.org/10.1089/nat.2018.0736

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Abstract

Short-interfering RNA (siRNA)-induced RNAi responses have great potential to treat a wide variety of human diseases from cancer to pandemic viral outbreaks to Parkinson's Disease. However, before siRNAs can become drugs, they must overcome a billion years of evolutionary defenses designed to keep invading RNAs on the outside cells from getting to the inside of cells. Not surprisingly, significant effort has been placed in developing a wide array of delivery technologies. Foremost of these has been the development of N-acetylgalactosamine (GalNAc) siRNA conjugates for delivery to liver. Tris-GalNAc binds to the Asialoglycoprotein receptor that is highly expressed on hepatocytes resulting in rapid endocytosis. While the exact mechanism of escape across the endosomal lipid bilayer membrane remains unknown, sufficient amounts of siRNAs enter the cytoplasm to induce robust, target selective RNAi responses in vivo. Multiple GalNAc-siRNA conjugate clinical trials, including two phase III trials, are currently underway by three biotech companies to treat a wide variety of diseases. GalNAc-siRNA conjugates are a simple solution to the siRNA delivery problem for liver hepatocytes and have shown the RNAi (and antisense oligonucleotide) field the path forward for targeting other tissue types.

StephenW

GalNAc-siRNA共轭物：引领RNAi治疗药物的传递途径
施普林格亚伦D.
和Dowdy Steven F.
在线发布：2018年6月1日https://doi.org/10.1089/nat.2018.0736

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摘要

短干扰RNA（siRNA）诱导的RNAi反应具有很大的潜力来治疗从癌症到大范围病毒爆发至帕金森氏病的各种人类疾病。然而，在他们成为药物之前，他们必须克服十亿年的进化防御机制，以防止侵入外部细胞的RNA进入细胞内部。毫不奇怪，在开发各种交付技术方面已经付出了巨大的努力。其中最重要的是开发用于递送至肝脏的N-乙酰半乳糖胺（GalNAc）siRNA缀合物。 Tris-GalNAc结合在肝细胞中高度表达的无唾液酸糖蛋白受体，导致快速胞吞作用。尽管内体脂质双层膜逃脱的确切机制仍然未知，但足够量的siRNA进入细胞质以在体内诱导稳健的，选择性的靶RNAi应答。目前正在进行多项GalNAc-siRNA结合物临床试验，包括两项III期试验，以解决各种疾病。 GalNAc-siRNA结合物是肝细胞siRNA递送的简单解决方案，并显示出RNAi（和反义寡核苷酸）领域。

StephenW

https://www.liebertpub.com/doi/10.1089/nat.2018.0736

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