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dc.contributor.authorLy, Socheata
dc.contributor.authorEcheverria, Dimas
dc.contributor.authorSousa, Jacquelyn
dc.contributor.authorKhvorova, Anastasia
dc.date2022-08-11T08:09:56.000
dc.date.accessioned2022-08-23T16:50:01Z
dc.date.available2022-08-23T16:50:01Z
dc.date.issued2020-09-04
dc.date.submitted2020-11-02
dc.identifier.citation<p>Ly S, Echeverria D, Sousa J, Khvorova A. Single-Stranded Phosphorothioated Regions Enhance Cellular Uptake of Cholesterol-Conjugated siRNA but Not Silencing Efficacy. Mol Ther Nucleic Acids. 2020 Sep 4;21:991-1005. doi: 10.1016/j.omtn.2020.07.029. Epub 2020 Jul 25. PMID: 32818923; PMCID: PMC7452107. <a href="https://doi.org/10.1016/j.omtn.2020.07.029">Link to article on publisher's site</a></p>
dc.identifier.issn2162-2531 (Linking)
dc.identifier.doi10.1016/j.omtn.2020.07.029
dc.identifier.pmid32818923
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41579
dc.description.abstractSmall interfering RNAs (siRNAs) have potential to silence virtually any disease-causing gene but require chemical modifications for delivery to the tissue and cell of interest. Previously, we demonstrated that asymmetric, phosphorothioate (PS)-modified, chemically stabilized, cholesterol-conjugated siRNAs, called hsiRNAs, support rapid cellular uptake and efficient mRNA silencing both in cultured cells and in vivo. Here, we systematically evaluated the impact of number, structure, and sequence context of PS-modified backbones on cellular uptake and RNAi-mediated silencing efficacy. We find that PS enhances cellular internalization in a sequence-dependent manner but only when present in a single-stranded but not double-stranded region. Furthermore, the observed increase in cellular internalization did not correlate with functional silencing improvement, indicating that PS-mediated uptake may drive compounds to non-productive sinks. Thus, the primary contributing factor of PS modifications to functional efficacy is likely stabilization rather than enhanced cellular uptake. A better understanding of the relative impact of different chemistries on productive versus non-productive uptake will assist in improved design of therapeutic RNAs.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=32818923&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright 2020 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectchemically modified siRNAs
dc.subjectcholesterol conjugated siRNAs
dc.subjectphosphorothioate
dc.subjectsiRNA trafficking
dc.subjectsiRNAs
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectCells
dc.subjectNucleic Acids, Nucleotides, and Nucleosides
dc.titleSingle-Stranded Phosphorothioated Regions Enhance Cellular Uptake of Cholesterol-Conjugated siRNA but Not Silencing Efficacy
dc.typeJournal Article
dc.source.journaltitleMolecular therapy. Nucleic acids
dc.source.volume21
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=5398&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/4369
dc.identifier.contextkey20053054
refterms.dateFOA2022-08-23T16:50:02Z
html.description.abstract<p>Small interfering RNAs (siRNAs) have potential to silence virtually any disease-causing gene but require chemical modifications for delivery to the tissue and cell of interest. Previously, we demonstrated that asymmetric, phosphorothioate (PS)-modified, chemically stabilized, cholesterol-conjugated siRNAs, called hsiRNAs, support rapid cellular uptake and efficient mRNA silencing both in cultured cells and in vivo. Here, we systematically evaluated the impact of number, structure, and sequence context of PS-modified backbones on cellular uptake and RNAi-mediated silencing efficacy. We find that PS enhances cellular internalization in a sequence-dependent manner but only when present in a single-stranded but not double-stranded region. Furthermore, the observed increase in cellular internalization did not correlate with functional silencing improvement, indicating that PS-mediated uptake may drive compounds to non-productive sinks. Thus, the primary contributing factor of PS modifications to functional efficacy is likely stabilization rather than enhanced cellular uptake. A better understanding of the relative impact of different chemistries on productive versus non-productive uptake will assist in improved design of therapeutic RNAs.</p>
dc.identifier.submissionpathoapubs/4369
dc.contributor.departmentRNA Therapeutics Institute
dc.source.pages991-1005


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Copyright 2020 The Authors.  This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Except where otherwise noted, this item's license is described as Copyright 2020 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).