Dr. Xiaobo Zhong
University of Connecticut
Department of Pharmaceutical Sciences
Friday, September 29, 2023
Room 120 – Meyerhoff Chemistry Building
Host: Dr. Kamal Seneviratne
“Better understand subcellular trafficking and distribution of siRNA drugsusing imaging systems”
Since the discovery of siRNAs in C. elegans as a mechanism in certain biological systems to interfere the function of an endogenous gene in 1998, siRNA has become a powerful tool to silencing expression of any gene in a sequence-specific manner. Later development of this Nobel Prize winning discovery offers a unique therapeutic platform to target disease-associated genes for the treatment of various rare life-threatening diseases as well as some common diseases. After two decades of growth and development supported by significant technological breakthroughs on chemical modifications and delivery platforms, the discovery and development of siRNA drugs have run into a fast pace with first drug patisiran approved by the FDA in 2018 and other four drugs givosiran, lumasiran, vutrisiran, and inclisiran approved between 2019 and 2021. It is expected in next few years 1-5 siRNA drugs may be approved by the FDA per year due to more than 200 candidate siRNA drugs in early to late clinical trials. Accompanying with success of the approved siRNA drugs, lack of therapeutic efficacy and intolerance of toxicity have made numerous tested siRNA drugs to be terminated in the development pipelines in last decades. Understanding subcellular trafficking and distribution of siRNA drugs is critical to improve therapeutic efficacy and reduce toxicity. Current knowledge on subcellular trafficking and distribution of siRNA drugs within a cell is generated based on the observation of fluorescence-labeled siRNA drugs and their co-localization with fluorescence-labeled antibodies against specific proteins in the compartment of early endosomes, late endosomes, and lysosomes using a conventional confocal microscopy. When optimally used, a conventional confocal microscopy may reach resolutions of 200 nm laterally and 500 nm axially. Size and kinetic of endosomes and lysosomes highly vary, but their diameter generally ranges between 200 and 500 nm. Under a conventional confocal microscopy, an endosome or lysosome normally appears as a blurred dot. It is hard to generate a clear image for subcellular distribution of siRNA drugs within endosomes and lysosomes by a conventional confocal microscopy. There is an urgent need to develop an image system with a much higher resolution and capability to visualize siRNA drugs within and out of endosomes and lysosomes. The seminar will discuss a potential imaging system for better understanding subcellular trafficking and distribution of siRNA drugs.