Enhancing siRNA efficacy in vivo with extended nucleic acid backbones.

IF 33.1 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Ken Yamada, Vignesh N Hariharan, Jillian Caiazzi, Rachael Miller, Chantal M Ferguson, Ellen Sapp, Hassan H Fakih, Qi Tang, Nozomi Yamada, Raymond C Furgal, Joseph D Paquette, Annabelle Biscans, Brianna M Bramato, Nicholas McHugh, Ashley Summers, Clemens Lochmann, Bruno M D C Godinho, Samuel Hildebrand, Samuel O Jackson, Dimas Echeverria, Matthew R Hassler, Julia F Alterman, Marian DiFiglia, Neil Aronin, Anastasia Khvorova
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引用次数: 0

Abstract

Therapeutic small interfering RNA (siRNA) requires sugar and backbone modifications to inhibit nuclease degradation. However, metabolic stabilization by phosphorothioate (PS), the only backbone chemistry used clinically, may be insufficient for targeting extrahepatic tissues. To improve oligonucleotide stabilization, we report the discovery, synthesis and characterization of extended nucleic acid (exNA) consisting of a methylene insertion between the 5'-C and 5'-OH of a nucleoside. exNA incorporation is compatible with common oligonucleotide synthetic protocols and the PS backbone, provides stabilization against 3' and 5' exonucleases and is tolerated at multiple oligonucleotide positions. A combined exNA-PS backbone enhances resistance to 3' exonuclease by ~32-fold over the conventional PS backbone and by >1,000-fold over the natural phosphodiester backbone, improving tissue exposure, tissue accumulation and efficacy in mice, both systemically and in the brain. The improved efficacy and durability imparted by exNA may enable therapeutic interventions in extrahepatic tissues, both with siRNA and with other oligonucleotides such as CRISPR guide RNA, antisense oligonucleotides, mRNA and tRNA.

Abstract Image

利用扩展核酸骨架增强 siRNA 在体内的功效。
治疗性小干扰 RNA(siRNA)需要糖和骨架修饰来抑制核酸酶降解。然而,硫代磷酸酯(PS)是临床上使用的唯一骨架化学物质,其代谢稳定性可能不足以靶向肝外组织。为了提高寡核苷酸的稳定性,我们报告了扩展核酸(exNA)的发现、合成和表征,它由核苷酸的 5'-C 和 5'-OH 之间的亚甲基插入物组成。exNA 的加入与常见的寡核苷酸合成方案和 PS 骨架兼容,可提供对 3' 和 5' 外切酶的稳定性,并可在多个寡核苷酸位置上耐受。与传统的 PS 骨架相比,exNA-PS 组合骨架对 3'外切酶的耐受性提高了约 32 倍,与天然磷酸二酯骨架相比,提高了超过 1,000 倍,从而改善了小鼠全身和大脑中的组织暴露、组织积累和药效。exNA 所带来的疗效和持久性的提高,可使对肝外组织的治疗干预成为可能,既可使用 siRNA,也可使用其他寡核苷酸,如 CRISPR 引导 RNA、反义寡核苷酸、mRNA 和 tRNA。
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来源期刊
Nature biotechnology
Nature biotechnology 工程技术-生物工程与应用微生物
CiteScore
63.00
自引率
1.70%
发文量
382
审稿时长
3 months
期刊介绍: Nature Biotechnology is a monthly journal that focuses on the science and business of biotechnology. It covers a wide range of topics including technology/methodology advancements in the biological, biomedical, agricultural, and environmental sciences. The journal also explores the commercial, political, ethical, legal, and societal aspects of this research. The journal serves researchers by providing peer-reviewed research papers in the field of biotechnology. It also serves the business community by delivering news about research developments. This approach ensures that both the scientific and business communities are well-informed and able to stay up-to-date on the latest advancements and opportunities in the field. Some key areas of interest in which the journal actively seeks research papers include molecular engineering of nucleic acids and proteins, molecular therapy, large-scale biology, computational biology, regenerative medicine, imaging technology, analytical biotechnology, applied immunology, food and agricultural biotechnology, and environmental biotechnology. In summary, Nature Biotechnology is a comprehensive journal that covers both the scientific and business aspects of biotechnology. It strives to provide researchers with valuable research papers and news while also delivering important scientific advancements to the business community.
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