Design of Lipid Nanoparticle Delivery Systems to Enable Therapeutic Applications of siRNA and mRNA
Sophisticated delivery systems are required in order to enable RNA-based macromolecules such as siRNA and mRNA to be used as therapeutics. These delivery systems must protect encapsulated RNA from degradation in the circulation, promote accumulation in target tissue and facilitate intracellular delivery into target cells following systemic administration. Lipid nanoparticles (LNP) are currently the leading delivery systems for satisfying these demands. In particular, LNP siRNA systems containing optimized ionizable cationic lipids have been shown to be highly potent and relatively non-toxic agents for silencing target genes in hepatocytes following i.v. injection. Fifty percent or greater target gene silencing in mice has been achieved for doses of less than 10 μg siRNA/kg body weight in combination with therapeutic indices of 1000 or higher. This has led to an LNP siRNA product in late stage clinical development to treat transthyretin-induced amyloidosis. In the case of organs such as the brain, direct injection of LNP siRNA systems is showing remarkable gene silencing potency and may have application for treatment of serious neurological disorders. Importantly, the LNP delivery systems developed for siRNA are also effective for delivery of mRNA and plasmids, further improvements in potency can be made by optimizing cationic lipid design for LNP mRNA systems. Such systems are showing promise for gene replacement therapies, vaccine applications and gene editing procedures. New approaches to abrogate immune responses to LNP formulations containing DNA and RNA polymers as well as new ways to enhance potency in non-hepatic tissues will be discussed.
Pieter R. Cullis
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
Pieter Cullis completed his PhD in Physics at the University of British Columbia (UBC) in 1972 and then pursued postdoctoral training in biochemistry at the University of Oxford and at the University of Utrecht. He joined the Department of Biochemistry and Molecular Biology at UBC in 1978 and was appointed professor in 1985. Dr. Cullis is an internationally recognized pioneer and leader in the field of lipids, biological membranes and liposomal drug delivery systems. His drug delivery systems have produced improved formulations of several cancer therapies and other drug agents. His lipid nanoparticles delivery system is a leading technology worldwide, enabling the therapeutic potential of siRNA.
He has received many awards, including the B.C. Science Council Gold Medal for Health Sciences in 1991, the Alec D. Bangham Award for contributions to liposome science and technology in 2000 and the B.C. Biotechnology Association award for Innovation and Achievement in 2002. He was elected a Fellow of the Royal Society of Canada in 2004, received the Leadership Award of the Canadian Society of Pharmaceutical Scientists in 2010 and was awarded the Prix Galien, Canada’s premier prize for achievements in pharmaceutical R&D, in 2011. Most recently he was also awarded the Milton Wong award for Leadership by LifeSciences BC in April 2015.
Dr. Cullis has been very active in the development of several biotechnology companies and his work has led to three drugs that have been approved in the U.S. and Europe for the treatment of cancer and ve more that have nished Phase I clinical studies. He is an inventor on over 40 patents.
Molecular Engineering and Sciences Seminar Series
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