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
{"title":"Enhancing siRNA efficacy in vivo with extended nucleic acid backbones.","authors":"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","doi":"10.1038/s41587-024-02336-7","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":null,"pages":null},"PeriodicalIF":33.1000,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature biotechnology","FirstCategoryId":"5","ListUrlMain":"https://doi.org/10.1038/s41587-024-02336-7","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
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.
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.
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