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Rational design of cationic lipids for siRNA delivery. 2010
Sean C Semple, and
Akin Akinc, and
Jianxin Chen, and
Ammen P Sandhu, and
Barbara L Mui, and
Connie K Cho, and
Dinah W Y Sah, and
Derrick Stebbing, and
Erin J Crosley, and
Ed Yaworski, and
Ismail M Hafez, and
J Robert Dorkin, and
June Qin, and
Kieu Lam, and
Kallanthottathil G Rajeev, and
Kim F Wong, and
Lloyd B Jeffs, and
Lubomir Nechev, and
Merete L Eisenhardt, and
Muthusamy Jayaraman, and
Mikameh Kazem, and
Martin A Maier, and
Masuna Srinivasulu, and
Michael J Weinstein, and
Qingmin Chen, and
Rene Alvarez, and
Scott A Barros, and
Soma De, and
Sandra K Klimuk, and
Todd Borland, and
Verbena Kosovrasti, and
William L Cantley, and
Ying K Tam, and
Muthiah Manoharan, and
Marco A Ciufolini, and
Mark A Tracy, and
Antonin de Fougerolles, and
Ian MacLachlan, and
Pieter R Cullis, and
Thomas D Madden, and
Michael J Hope
Tekmira Pharmaceuticals, Burnaby, British Columbia, Canada. ssemple@tekmirapharm.com
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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