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- Title
Rational design of cationic lipids for siRNA delivery.
- Authors
Semple, Sean C.; Akinc, Akin; Chen, Jianxin; Sandhu, Ammen P.; Mui, Barbara L.; Cho, Connie K.; Sah, Dinah W. Y.; Stebbing, Derrick; Crosley, Erin J.; Yaworski, Ed; Hafez, Ismail M.; Dorkin, J. Robert; Qin, June; Lam, Kieu; Rajeev, Kallanthottathil G.; Wong, Kim F.; Jeffs, Lloyd B.; Nechev, Lubomir; Eisenhardt, Merete L.; Jayaraman, Muthusamy
- Abstract
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.
- Subjects
LIPIDS; SMALL interfering RNA; NUCLEIC acids; LABORATORY rodents; PRIMATES as laboratory animals; GENE silencing
- Publication
Nature Biotechnology, 2010, Vol 28, Issue 2, p172
- ISSN
1087-0156
- Publication type
Article
- DOI
10.1038/nbt.1602