The chemical structure and phosphorothioate content of hydrophobically modified siRNAs impact extrahepatic distribution and efficacy
Authors
Biscans, AnnabelleCaiazzi, Jillian
Davis, Sarah M
McHugh, Nicholas
Sousa, Jacquelyn
Khvorova, Anastasia
Student Authors
Sarah M. DavisAcademic Program
InterdisciplinaryUMass Chan Affiliations
Graduate School of Biomedical SciencesProgram in Molecular Medicine
RNA Therapeutics Institute
Document Type
Journal ArticlePublication Date
2020-08-20Keywords
Small interfering RNAssiRNAs
liver diseases
delivery
chemical structure
Biochemistry
Chemistry
Digestive System Diseases
Molecular Biology
Nucleic Acids, Nucleotides, and Nucleosides
Structural Biology
Metadata
Show full item recordAbstract
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.Source
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. Link to article on publisher's site
DOI
10.1093/nar/gkaa595Permanent Link to this Item
http://hdl.handle.net/20.500.14038/41547PubMed ID
32672813Related Resources
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.Distribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1093/nar/gkaa595
Scopus Count
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.