Abstract
The safe and effective delivery of RNA interference (RNAi) therapeutics remains an important challenge for clinical development. The diversity of current delivery materials remains limited, in part because of their slow, multi-step syntheses. Here we describe a new class of lipid-like delivery molecules, termed lipidoids, as delivery agents for RNAi therapeutics. Chemical methods were developed to allow the rapid synthesis of a large library of over 1,200 structurally diverse lipidoids. From this library, we identified lipidoids that facilitate high levels of specific silencing of endogenous gene transcripts when formulated with either double-stranded small interfering RNA (siRNA) or single-stranded antisense 2′-O-methyl (2′-OMe) oligoribonucleotides targeting microRNA (miRNA). The safety and efficacy of lipidoids were evaluated in three animal models: mice, rats and nonhuman primates. The studies reported here suggest that these materials may have broad utility for both local and systemic delivery of RNA therapeutics.
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Acknowledgements
The authors would like to thank funding by the National Institutes of Health grant R01 EB00244. A.Z. would like to thank the Swiss National Science Foundation for his postdoctoral fellowship. We would also like to thank John Maraganore for helpful comments and Maryellen Duckman for assistance with manuscript preparation.
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A.A., R.A., A.B., T.B., A.d.F., J.R.D., K.N.J., M.J., V.K., M.M., L.N., J.Q., T.R., D.R., K.G.R., D.W.Y.S., I.T. and S.Z. are current employees of Alnylam Pharmaceuticals. R.C., M.J., J.S. and H.-P.V. are former employees of Alnylam Pharmaceuticals.
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Akinc, A., Zumbuehl, A., Goldberg, M. et al. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nat Biotechnol 26, 561–569 (2008). https://doi.org/10.1038/nbt1402
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DOI: https://doi.org/10.1038/nbt1402
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