2′-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity

小干扰RNA 基因沉默 RNA干扰 反式siRNA 癌症研究 化学 效力 核糖核酸 生物 细胞生物学 体外 生物化学 基因
作者
Sherry Y. Wu,Xianbin Yang,Kshipra M. Gharpure,Hiroto Hatakeyama,Martin Egli,Michael H. McGuire,Archana S. Nagaraja,Takahito Miyake,Rajesha Rupaimoole,Chad V. Pecot,Morgan Taylor,Sunila Pradeep,Małgorzata Sierant,Cristian Rodriguez‐Aguayo,Hyun Jin Choi,Rebecca A. Previs,Guillermo N. Armaiz-Peña,Li Huang,Carlos Martinez,Tom Hassell,Cristina Ivan,Vasudha Sehgal,Richa Singhania,Hee Dong Han,Chang Su,Ji Hoon Kim,Heather J. Dalton,Chandra Kovvali,Khandan Keyomarsi,Nigel A.J. McMillan,Willem W. Overwijk,Jinsong Liu,Ju‐Seog Lee,Keith Baggerly,Gabriel López-Berestein,Prahlad T. Ram,Barbara Nawrot,Anil K. Sood
出处
期刊:Nature Communications [Springer Nature]
卷期号:5 (1) 被引量:115
标识
DOI:10.1038/ncomms4459
摘要

Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation. Here, we report a chemical modification, consisting of phosphorodithioate (PS2) and 2′-O-Methyl (2′-OMe) MePS2 on one nucleotide that significantly enhances potency and resistance to degradation for various siRNAs. We find enhanced potency stems from an unforeseen increase in siRNA loading to the RNA-induced silencing complex, likely due to the unique interaction mediated by 2′-OMe and PS2. We demonstrate the therapeutic utility of MePS2 siRNAs in chemoresistant ovarian cancer mouse models via targeting GRAM domain containing 1B (GRAMD1B), a protein involved in chemoresistance. GRAMD1B silencing is achieved in tumours following MePS2-modified siRNA treatment, leading to a synergistic anti-tumour effect in combination with paclitaxel. Given the previously limited success in enhancing siRNA potency with chemically modified siRNAs, our findings represent an important advance in siRNA design with the potential for application in numerous cancer types. Short interfering siRNAs—siRNAs—have therapeutic potential in the treatment of disease; however, their delivery to target tissues is difficult. Here, Wu et al. chemically modify siRNAs and show that this improves loading into the siRNA silencing machinery and thus efficacy in eliminating cancer cells in mice.
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