Development of the next generation of lipid nanoparticles for gene therapy

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Lipid nanoparticles (LNPs) are a revolutionary tool for drug delivery, functional genomics and other applications in biotechnology and medicine. They are on the verge of enabling one of the dream applications of personalized medicine: individual gene therapy in diseases such as cancer. Knowledge of the "rogue" genes responsible for tumour growth is substantial but there remains a number of significant obstacles to effectively turning these genes off or "silencing" them. The most promising gene therapy approach utilizes short pieces of double stranded RNA (siRNA) whose sequence allows it to bind to the cancer gene's messenger RNA, after which a natural cellular mechanism degrades it. Following intracellular delivery siRNAs have demonstrated abilities to silence specific genes in vitro. However, the use of siRNA in vivo requires sophisticated delivery technologies, since "naked" siRNAs are rapidly broken down in the circulation, do not accumulate at disease sites and cannot penetrate target cell membranes to reach their intracellular sites of action. Encapsulating siRNA in an LNP protects the siRNA from degradation in the bloodstream, and enables the internalization of the siRNA within the cell via endocytosis. However, considerable work remains to increase the practical use of LNPs. The nanostructure of the LNP siRNA systems and the functional roles of the five different lipid components they contain are not well understood, impeding efforts to develop next generation systems that are stable, can be targeted to different tissues, are straightforward to manufacture, and meet regulatory requirements. In this project, we will use computer modelling and biophysical characterization to investigate the role of the different components in determining the structure, size, targeting properties and the endosomal release mechanism of LNPs. We will test our knowledge in the design and manufacture of new LNPs. This will lead to improved rational design technology for LNPs that will greatly expand their use as anti-cancer drugs and functional genomics tools, with extensive opportunities for commercialization of both technology, through our partner Precision NanoSystems, and the development of drugs for specific forms of cancer.