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dc.contributor.authorBiscans, Annabelle
dc.contributor.authorCaiazzi, Jillian
dc.contributor.authorDavis, Sarah M
dc.contributor.authorMcHugh, Nicholas
dc.contributor.authorSousa, Jacquelyn
dc.contributor.authorKhvorova, Anastasia
dc.date2022-08-11T08:09:56.000
dc.date.accessioned2022-08-23T16:49:51Z
dc.date.available2022-08-23T16:49:51Z
dc.date.issued2020-08-20
dc.date.submitted2020-09-29
dc.identifier.citation<p>Biscans A, Caiazzi J, Davis S, McHugh N, Sousa J, Khvorova A. The chemical structure and phosphorothioate content of hydrophobically modified siRNAs impact extrahepatic distribution and efficacy. Nucleic Acids Res. 2020 Aug 20;48(14):7665-7680. doi: 10.1093/nar/gkaa595. PMID: 32672813; PMCID: PMC7430635. <a href="https://doi.org/10.1093/nar/gkaa595">Link to article on publisher's site</a></p>
dc.identifier.issn0305-1048 (Linking)
dc.identifier.doi10.1093/nar/gkaa595
dc.identifier.pmid32672813
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41547
dc.description.abstractSmall interfering RNAs (siRNAs) have revolutionized the treatment of liver diseases. However, robust siRNA delivery to other tissues represents a major technological need. Conjugating lipids (e.g. docosanoic acid, DCA) to siRNA supports extrahepatic delivery, but tissue accumulation and gene silencing efficacy are lower than that achieved in liver by clinical-stage compounds. The chemical structure of conjugated siRNA may significantly impact invivo efficacy, particularly in tissues with lower compound accumulation. Here, we report the first systematic evaluation of the impact of siRNA scaffold-i.e. structure, phosphorothioate (PS) content, linker composition-on DCA-conjugated siRNA delivery and efficacy in vivo. We found that structural asymmetry (e.g. 5- or 2-nt overhang) has no impact on accumulation, but is a principal factor for enhancing activity in extrahepatic tissues. Similarly, linker chemistry (cleavable versus stable) altered activity, but not accumulation. In contrast, increasing PS content enhanced accumulation of asymmetric compounds, but negatively impacted efficacy. Our findings suggest that siRNA tissue accumulation does not fully define efficacy, and that the impact of siRNA chemical structure on activity is driven by intracellular re-distribution and endosomal escape. Fine-tuning siRNA chemical structure for optimal extrahepatic efficacy is a critical next step for the progression of therapeutic RNAi applications beyond liver.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=32672813&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rights© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectSmall interfering RNAs
dc.subjectsiRNAs
dc.subjectliver diseases
dc.subjectdelivery
dc.subjectchemical structure
dc.subjectBiochemistry
dc.subjectChemistry
dc.subjectDigestive System Diseases
dc.subjectMolecular Biology
dc.subjectNucleic Acids, Nucleotides, and Nucleosides
dc.subjectStructural Biology
dc.titleThe chemical structure and phosphorothioate content of hydrophobically modified siRNAs impact extrahepatic distribution and efficacy
dc.typeJournal Article
dc.source.journaltitleNucleic acids research
dc.source.volume48
dc.source.issue14
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=5364&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/4337
dc.identifier.contextkey19587005
refterms.dateFOA2022-08-23T16:49:52Z
html.description.abstract<p>Small interfering RNAs (siRNAs) have revolutionized the treatment of liver diseases. However, robust siRNA delivery to other tissues represents a major technological need. Conjugating lipids (e.g. docosanoic acid, DCA) to siRNA supports extrahepatic delivery, but tissue accumulation and gene silencing efficacy are lower than that achieved in liver by clinical-stage compounds. The chemical structure of conjugated siRNA may significantly impact invivo efficacy, particularly in tissues with lower compound accumulation. Here, we report the first systematic evaluation of the impact of siRNA scaffold-i.e. structure, phosphorothioate (PS) content, linker composition-on DCA-conjugated siRNA delivery and efficacy in vivo. We found that structural asymmetry (e.g. 5- or 2-nt overhang) has no impact on accumulation, but is a principal factor for enhancing activity in extrahepatic tissues. Similarly, linker chemistry (cleavable versus stable) altered activity, but not accumulation. In contrast, increasing PS content enhanced accumulation of asymmetric compounds, but negatively impacted efficacy. Our findings suggest that siRNA tissue accumulation does not fully define efficacy, and that the impact of siRNA chemical structure on activity is driven by intracellular re-distribution and endosomal escape. Fine-tuning siRNA chemical structure for optimal extrahepatic efficacy is a critical next step for the progression of therapeutic RNAi applications beyond liver.</p>
dc.identifier.submissionpathoapubs/4337
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentRNA Therapeutics Institute
dc.source.pages7665-7680
dc.contributor.studentSarah M. Davis
dc.description.thesisprogramInterdisciplinary


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© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Except where otherwise noted, this item's license is described as © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.