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Enhancing siRNA efficacy in vivo with extended nucleic acid backbones.
Yamada, Ken; Hariharan, Vignesh N; Caiazzi, Jillian; Miller, Rachael; Ferguson, Chantal M; Sapp, Ellen; Fakih, Hassan H; Tang, Qi; Yamada, Nozomi; Furgal, Raymond C; Paquette, Joseph D; Biscans, Annabelle; Bramato, Brianna M; McHugh, Nicholas; Summers, Ashley; Lochmann, Clemens; Godinho, Bruno M D C; Hildebrand, Samuel; Jackson, Samuel O; Echeverria, Dimas; Hassler, Matthew R; Alterman, Julia F; DiFiglia, Marian; Aronin, Neil; Khvorova, Anastasia.
Afiliación
  • Yamada K; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA. ken.yamada@umassmed.edu.
  • Hariharan VN; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Caiazzi J; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Miller R; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Ferguson CM; Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Sapp E; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Fakih HH; Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Tang Q; Department of Neurology, Harvard Medical School and Mass General Institute for Neurodegenerative Disease, Charlestown, MA, USA.
  • Yamada N; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Furgal RC; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Paquette JD; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Biscans A; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Bramato BM; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • McHugh N; Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Summers A; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Lochmann C; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Godinho BMDC; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Hildebrand S; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Jackson SO; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Echeverria D; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Hassler MR; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • DiFiglia M; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Aronin N; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Khvorova A; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Nat Biotechnol ; 2024 Aug 01.
Article en En | MEDLINE | ID: mdl-39090305
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Nat Biotechnol Asunto de la revista: BIOTECNOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Nat Biotechnol Asunto de la revista: BIOTECNOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos