Associate Professor University College Cork CORK, Ireland
Circular RNAs (circRNAs) are a new class of non-coding RNAs, characterized by a covalently closed-loop structure and produced from genes through an alternative form of splicing, called back splicing. The lack of free ends necessary for exonuclease-mediated degradation, including 5′ Cap and 3′poly(A) tail, makes circRNAs significantly more stable, extending their half-life intracellularly and in blood as compared to their linear counterparts. They were also shown to possess unique roles and structural features and have been implicated in several human diseases, hinting at their potential for therapeutic applications. We developed methods for the circularization and purification of synthetic circRNAs and pioneered the use of these circRNAs for robust and stable protein expression in eukaryotic cells to address the short half-life of mRNA in biological systems. Compared to modified linear messenger RNAs (mRNA), synthetic circRNAs have a longer intracellular half-life which allows sustained translation driven by the internal ribosome entry site, both in vitro and in mice after injection of circRNA formulated into lipid nanoparticles. In contrast to linear mRNAs unmodified synthetic circRNA can also bypass the cellular RNA sensors such as RIG-I and Toll-like receptor, thereby avoiding unwanted immune responses in cells and mice. Currently our research is focused on addressing a significant gap in the knowledge on the utility of synthetic circular RNAs for translational research and developing methods to deliver them inside the cells to help realize their therapeutic potential.
