Lipid nanoparticles (LNP) are currently the leading delivery systems for in vivo delivery of siRNA. We have designed ionizable cationic lipids with pKa values between 6 and 7 that allow siRNA loading at low pH but also produce LNP siRNA systems that exhibit low surface charge at physiological pH values. It is shown that ionizable cationic lipids with optimized pKa values and maximized bilayer destabilizing capabilities leads to highly potent LNP siRNA delivery systems that exhibit gene silencing activity at i.v. doses of less than 10 �g siRNA/kg body weight for silencing hepatocyte target genes in animal models. This is currently the world-leading �gold standard� for the potency of siRNA delivery systems in vivo. Clinical validation of these LNP siRNA systems for silencing the liver targets PCSK9 (to treat hypercholesterolemia) and transthyretin (TTR

Design of lipid nanoparticle ystems for the systemic delivery of siRNA

245th National Meeting (2013)

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