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dc.contributor.authorBiscans, Annabelle
dc.contributor.authorColes, Andrew H.
dc.contributor.authorHaraszti, Reka A
dc.contributor.authorEcheverria, Dimas
dc.contributor.authorHassler, Matthew R
dc.contributor.authorOsborn, Maire F.
dc.contributor.authorKhvorova, Anastasia
dc.date2022-08-11T08:10:52.000
dc.date.accessioned2022-08-23T17:22:55Z
dc.date.available2022-08-23T17:22:55Z
dc.date.issued2019-02-20
dc.date.submitted2019-06-03
dc.identifier.citation<p>Nucleic Acids Res. 2019 Feb 20;47(3):1082-1096. doi: 10.1093/nar/gky1239. <a href="https://doi.org/10.1093/nar/gky1239">Link to article on publisher's site</a></p>
dc.identifier.issn0305-1048 (Linking)
dc.identifier.doi10.1093/nar/gky1239
dc.identifier.pmid30544191
dc.identifier.urihttp://hdl.handle.net/20.500.14038/48846
dc.description.abstractSmall interfering RNA (siRNA)-based therapies are proving to be efficient for treating liver-associated disorders. However, extra-hepatic delivery remains challenging, limiting therapeutic siRNA utility. We synthesized a panel of fifteen lipid-conjugated siRNAs and systematically evaluated the impact of conjugate on siRNA tissue distribution and efficacy. Generally, conjugate hydrophobicity defines the degree of clearance and the liver-to-kidney distribution profile. In addition to primary clearance tissues, several conjugates achieve significant siRNA accumulation in muscle, lung, heart, adrenal glands and fat. Oligonucleotide distribution to extra-hepatic tissues with some conjugates was significantly higher than with cholesterol, a well studied conjugate, suggesting that altering conjugate structure can enhance extra-hepatic delivery. These conjugated siRNAs enable functional gene silencing in lung, muscle, fat, heart and adrenal gland. Required levels for productive silencing vary (5-200 mug/g) per tissue, suggesting that the chemical nature of conjugates impacts tissue-dependent cellular/intracellular trafficking mechanisms. The collection of conjugated siRNA described here enables functional gene modulation in vivo in several extra-hepatic tissues opening these tissues for gene expression modulation. A systemic evaluation of a panel of conjugated siRNA, as reported here, has not previously been investigated and shows that chemical engineering of lipid siRNAs is essential to advance the RNA therapeutic field.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=30544191&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright The Author(s) 2018. 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 RNA
dc.subjectsiRNA
dc.subjectlipids
dc.subjecttherapeutics
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectGenetic Phenomena
dc.subjectGenetics and Genomics
dc.subjectLipids
dc.subjectNucleic Acids, Nucleotides, and Nucleosides
dc.titleDiverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo
dc.typeJournal Article
dc.source.journaltitleNucleic acids research
dc.source.volume47
dc.source.issue3
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1053&amp;context=rti_pubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/rti_pubs/54
dc.identifier.contextkey14647626
refterms.dateFOA2022-08-23T17:22:55Z
html.description.abstract<p>Small interfering RNA (siRNA)-based therapies are proving to be efficient for treating liver-associated disorders. However, extra-hepatic delivery remains challenging, limiting therapeutic siRNA utility. We synthesized a panel of fifteen lipid-conjugated siRNAs and systematically evaluated the impact of conjugate on siRNA tissue distribution and efficacy. Generally, conjugate hydrophobicity defines the degree of clearance and the liver-to-kidney distribution profile. In addition to primary clearance tissues, several conjugates achieve significant siRNA accumulation in muscle, lung, heart, adrenal glands and fat. Oligonucleotide distribution to extra-hepatic tissues with some conjugates was significantly higher than with cholesterol, a well studied conjugate, suggesting that altering conjugate structure can enhance extra-hepatic delivery. These conjugated siRNAs enable functional gene silencing in lung, muscle, fat, heart and adrenal gland. Required levels for productive silencing vary (5-200 mug/g) per tissue, suggesting that the chemical nature of conjugates impacts tissue-dependent cellular/intracellular trafficking mechanisms. The collection of conjugated siRNA described here enables functional gene modulation in vivo in several extra-hepatic tissues opening these tissues for gene expression modulation. A systemic evaluation of a panel of conjugated siRNA, as reported here, has not previously been investigated and shows that chemical engineering of lipid siRNAs is essential to advance the RNA therapeutic field.</p>
dc.identifier.submissionpathrti_pubs/54
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentRNA Therapeutics Institute
dc.source.pages1082-1096


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Copyright The Author(s) 2018. 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 Copyright The Author(s) 2018. 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.