Conjugate siRNAs for Hepatic Targets

Since unmodified siRNAs are rapidly eliminated and do not achieve significant tissue distribution upon systemic administration (Soutschek et al., 2004), various targeted delivery strategies target distribution to tissues and facilitate uptake of siRNAs into a relevant cell type. One approach used successfully in animal models (including rodents and nonhuman primates [NHP]) and humans employs intravenous (IV) delivery of siRNA in lipid nanoparticle (LNP) formulations (Soutschek et al., 2004 Morrissey et al., 2005  

Drug Discovery Toxicology From Target Assessment to Translational Biomarkers, First Edition. Edited by Yvonne Will, J. Eric McDuffie, Andrew J. Olaharski, and Brandon D. Jeffy. 

DISCOVERY AND DEVELOPMENT STRATEGIES FOR SMALL INTERFERING RNAs 

This chapter broadly describes the lead optimization activities relevant to the development of novel conjugate siRNA therapeutics for hepatic targets via subcutaneous administration. For specific information regarding other therapeutic oligonucleotide technologies (e.g., antisense, aptamer, CpG, anti-miR), specific nanoparticle-based delivery systems, or non-hepatic targeting, readers are directed elsewhere (Bennett and Swayze, 2010 Kole et al., 2012). 

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