We adopted a rational approach to design cationic lipids for use in formulations to deliver small interfering RNA (siRNA). Starting with the ionizable cationic lipid 1,2-dilinoleyloxy-3-dimethylaminopropane (DLinDMA), a key lipid component of stable nucleic acid lipid particles (SNALP) as a benchmark, we used the proposed in vivo mechanism of action of ionizable cationic lipids to guide the design of DLinDMA-based lipids with superior delivery capacity. The best-performing lipid recovered after screening (DLin-KC2-DMA) was formulated and characterized in SNALP and demonstrated to have in vivo activity at siRNA doses as low as 0.01 mg/kg in rodents and 0.1 mg/kg in nonhuman primates. To our knowledge, this represents a substantial improvement over previous reports of in vivo endogenous hepatic gene silencing.
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The authors thank K. McClintock for assistance with animal studies. The authors also thank the Centre for Drug Research and Development at the University of British Columbia for use of the NMR facilities and M. Heller for his expert assistance in setting up the 31P-NMR experiments.
Authors are employees of Alnylam, Tekmira, or Alcana or receive funding from Alnylam.
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Semple, S., Akinc, A., Chen, J. et al. Rational design of cationic lipids for siRNA delivery. Nat Biotechnol 28, 172–176 (2010). https://doi.org/10.1038/nbt.1602
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