RNA Therapeutics Institute; Program in Molecular Medicine
Biochemistry, Biophysics, and Structural Biology | Genetic Phenomena | Genetics and Genomics | Lipids | Nucleic Acids, Nucleotides, and Nucleosides
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.
Small interfering RNA, siRNA, lipids, therapeutics
Rights and Permissions
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.
DOI of Published Version
Nucleic Acids Res. 2019 Feb 20;47(3):1082-1096. doi: 10.1093/nar/gky1239. Link to article on publisher's site
Nucleic acids research
Biscans, Annabelle; Coles, Andrew H.; Haraszti, Reka A.; Echeverria, Dimas; Hassler, Matthew R.; Osborn, Maire F.; and Khvorova, Anastasia, "Diverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo" (2019). RNA Therapeutics Institute Publications. 54.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.