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Comparison of partially and fully chemically-modified siRNA in conjugate-mediated delivery in vivo.
Hassler, Matthew R; Turanov, Anton A; Alterman, Julia F; Haraszti, Reka A; Coles, Andrew H; Osborn, Maire F; Echeverria, Dimas; Nikan, Mehran; Salomon, William E; Roux, Loïc; Godinho, Bruno M D C; Davis, Sarah M; Morrissey, David V; Zamore, Phillip D; Karumanchi, S Ananth; Moore, Melissa J; Aronin, Neil; Khvorova, Anastasia.
Affiliation
  • Hassler MR; RNA Therapeutics Institute, University of Massachusetts Medical School, USA.
  • Turanov AA; RNA Therapeutics Institute, University of Massachusetts Medical School, USA.
  • Alterman JF; RNA Therapeutics Institute, University of Massachusetts Medical School, USA.
  • Haraszti RA; RNA Therapeutics Institute, University of Massachusetts Medical School, USA.
  • Coles AH; RNA Therapeutics Institute, University of Massachusetts Medical School, USA.
  • Osborn MF; RNA Therapeutics Institute, University of Massachusetts Medical School, USA.
  • Echeverria D; RNA Therapeutics Institute, University of Massachusetts Medical School, USA.
  • Nikan M; RNA Therapeutics Institute, University of Massachusetts Medical School, USA.
  • Salomon WE; RNA Therapeutics Institute, University of Massachusetts Medical School, USA.
  • Roux L; RNA Therapeutics Institute, University of Massachusetts Medical School, USA.
  • Godinho BMDC; RNA Therapeutics Institute, University of Massachusetts Medical School, USA.
  • Davis SM; RNA Therapeutics Institute, University of Massachusetts Medical School, USA.
  • Morrissey DV; Novartis Institute of Biomedical Research, USA.
  • Zamore PD; RNA Therapeutics Institute, University of Massachusetts Medical School, USA.
  • Karumanchi SA; Beth Israel Deaconess Medical Center, Harvard Medical School, USA.
  • Moore MJ; RNA Therapeutics Institute, University of Massachusetts Medical School, USA.
  • Aronin N; RNA Therapeutics Institute, University of Massachusetts Medical School, USA.
  • Khvorova A; Department of Medicine, University of Massachusetts Medical School, USA.
Nucleic Acids Res ; 46(5): 2185-2196, 2018 03 16.
Article in En | MEDLINE | ID: mdl-29432571
Small interfering RNA (siRNA)-based drugs require chemical modifications or formulation to promote stability, minimize innate immunity, and enable delivery to target tissues. Partially modified siRNAs (up to 70% of the nucleotides) provide significant stabilization in vitro and are commercially available; thus are commonly used to evaluate efficacy of bio-conjugates for in vivo delivery. In contrast, most clinically-advanced non-formulated compounds, using conjugation as a delivery strategy, are fully chemically modified (100% of nucleotides). Here, we compare partially and fully chemically modified siRNAs in conjugate mediated delivery. We show that fully modified siRNAs are retained at 100x greater levels in various tissues, independently of the nature of the conjugate or siRNA sequence, and support productive mRNA silencing. Thus, fully chemically stabilized siRNAs may provide a better platform to identify novel moieties (peptides, aptamers, small molecules) for targeted RNAi delivery.
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Full text: 1 Database: MEDLINE Main subject: RNA Processing, Post-Transcriptional / Drug Delivery Systems / RNA, Small Interfering / RNA Interference Limits: Animals / Female / Humans Language: En Year: 2018 Type: Article
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Full text: 1 Database: MEDLINE Main subject: RNA Processing, Post-Transcriptional / Drug Delivery Systems / RNA, Small Interfering / RNA Interference Limits: Animals / Female / Humans Language: En Year: 2018 Type: Article