2. Academic Validation
  3. Rational design of cationic lipids for siRNA delivery

Rational design of cationic lipids for siRNA delivery

  • Nat Biotechnol. 2010 Feb;28(2):172-6. doi: 10.1038/nbt.1602.
Sean C Semple 1,  Akin Akinc,  Jianxin Chen,  Ammen P Sandhu,  Barbara L Mui,  Connie K Cho,  Dinah W Y Sah,  Derrick Stebbing,  Erin J Crosley,  Ed Yaworski,  Ismail M Hafez,  J Robert Dorkin,  June Qin,  Kieu Lam,  Kallanthottathil G Rajeev,  Kim F Wong,  Lloyd B Jeffs,  Lubomir Nechev,  Merete L Eisenhardt,  Muthusamy Jayaraman,  Mikameh Kazem,  Martin A Maier,  Masuna Srinivasulu,  Michael J Weinstein,  Qingmin Chen,  Rene Alvarez,  Scott A Barros,  Soma De,  Sandra K Klimuk,  Todd Borland,  Verbena Kosovrasti,  William L Cantley,  Ying K Tam,  Muthiah Manoharan,  Marco A Ciufolini,  Mark A Tracy,  Antonin de Fougerolles,  Ian MacLachlan,  Pieter R Cullis,  Thomas D Madden,  Michael J Hope
Affiliations

Affiliation

  • 1 Tekmira Pharmaceuticals, Burnaby, British Columbia, Canada. ssemple@tekmirapharm.com
PMID: 20081866 DOI: 10.1038/nbt.1602
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.

Figures
Products