RNA Therapeutics Institute; Department of Medicine; Program in Molecular Medicine
Biochemistry | Medicinal-Pharmaceutical Chemistry | Molecular Biology | Nucleic Acids, Nucleotides, and Nucleosides
Small interfering RNA (siRNA)-based drugs require chemical modifications or formulation to promote stability, minimize innate immunity, and enable delivery to target tissues. Partially modified siRNAs (up to 70% of the nucleotides) provide significant stabilization in vitro and are commercially available; thus are commonly used to evaluate efficacy of bio-conjugates for in vivo delivery. In contrast, most clinically-advanced non-formulated compounds, using conjugation as a delivery strategy, are fully chemically modified (100% of nucleotides). Here, we compare partially and fully chemically modified siRNAs in conjugate mediated delivery. We show that fully modified siRNAs are retained at 100x greater levels in various tissues, independently of the nature of the conjugate or siRNA sequence, and support productive mRNA silencing. Thus, fully chemically stabilized siRNAs may provide a better platform to identify novel moieties (peptides, aptamers, small molecules) for targeted RNAi delivery.
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© 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-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact email@example.com.
DOI of Published Version
Nucleic Acids Res. 2018 Feb 8. doi: 10.1093/nar/gky037. [Epub ahead of print] Link to article on publisher's website
Nucleic acids research
Hassler, Matthew R.; Turanov, Anton A.; Alterman, Julia F.; Haraszti, Reka A.; Coles, Andrew H.; Osborn, Maire F.; Echeverria, Dimas; Nikan, Mehran; Salomon, William E.; Roux, Loic; Godinho, Bruno M. D. C.; Davis, Sarah M.; Morrissey, David V.; Zamore, Phillip D.; Karumanchi, S. Ananth; Moore, Melissa J.; Aronin, Neil; and Khvorova, Anastasia, "Comparison of partially and fully chemically-modified siRNA in conjugate-mediated delivery in vivo" (2018). Open Access Articles. 3275.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License