593. Progress towards DNA-Based and siRNA Therapeutics

Abstract

The development of clinically viable, synthetic non-viral delivery systems for targeted delivery of DNA to cells has been a major preoccupation of many laboratories world-wide. In our hands, we have been attempting the rational design and development of self-assembly, synthetic complexes involving cationic liposomes (L) and nucleic acids such as plasmid DNA (pDNA, D), for this purpose. However, even after our development of the non-viral vector platform system known as liposome:mu:DNA (LMD), significant problems appear to remain before clinically viable DNA delivery may be realized. By contrast, we have found that our cationic liposome/lipid-based vector systems appear to be much better suited for the delivery of siRNA to cells (siFection). Drawing upon our experiences with pDNA delivery to cells (transfection), IC-Vec has developed a proprietary, self-assembly ABCD nanoparticle technology (CONZENTRx|[trade]|) that is well adapted for siFection in vitro and in vivo. Formulations are reproducible and scalable in all cases. For in vitro use, we have developed a potent new cationic liposome system (siFECTamine|[reg]|) that combines with siRNA (siR) to give LsiR particles (AB system) for siFection at very low siRNA doses with negligible toxicity. This simple AB system may then be upgraded for in vivo applications by using a highly selective and efficient proprietary bioconjugation chemistry to introduce chemical components for biological stability (C layer) and/or for biological targeting (D layer). The resulting nanoparticles (siFECTplus|[trade]|; ABC, ABD or ABCD systems) are closely size controlled and proof of concept studies demonstrate that purpose-designed siFECTplus|[trade]| nanoparticles (70nm) are able to deliver siRNA to murine liver in vivo causing substantial and specific protein down regulation with minimal detectable toxicity. CONZENTRx|[trade]| formulations make use of tool-kits of chemical components ensuring that siFECTplus|[trade]| nanoparticles can be tailor-made for individual siRNA delivery requirements. In collaboration with our strategic alliance partner, RNAi Co., the future for siRNA therapeutics looks promising. Data from further proof of concept studies in animal models will be presented demonstrating siRNA therapeutic approaches for the treatment of hepatitis and other diseases, assisted by siFECTplus|[trade]| nanoparticle delivery.