Novel RNA Device – Designing Functional Nucleic Acids (No. Riboswitch)
Novel mammalian riboswitches for inducible expression of exogenous transgenes.
RNA devices, such as riboswitches, expands the possible tools to assist in therapeutic applications. Living systems use RNA sequences known as riboswitches to detect the concentrations of small-molecule metabolites within cells and to regulate the expression of genes that produce these metabolites. Like their natural counterparts, synthetic riboswitches also regulate gene expression in response to small molecules. Because synthetic riboswitches can be engineered to respond to nonendogenous small molecules, they are powerful tools for understanding and reprogramming cellular behavior for therapeutic responses. Successful development of new engineered riboswitches, however, is not only dependent on an innovative design but also necessitates a two step process: first, an in vitro selection which results in aptamers with high affinity binding to a desired ligand and second, a subsequent screen to identify RNAs with a desired functionality within cells. Here we present promising riboswitch protocols developed by a group of researchers led by Prof. Yohei Yokobayashi to overcome the above mentioned challenges.
- Gene therapy
- Cell therapy
- Compact riboswitch
- Chemical regulation of gene expression in bacteria and mammalian cells
The technology is based on developing novel mammalian riboswitches for inducible expression of transgenes in mammalian cells. Professor Yokobayashi’s riboswitches are based on (self-cleaving) ribozyme-aptamer fusion (=aptazyme) embedded in the 3’ UTR of the transgene mRNA whose expression is regulated (e.g. Mustafina et al. 2020, Mustafina et al. 2021). There are several possible directions to further improve the riboswitches in therapeutic applications. 1) Keep screening additional aptazyme variants. 2) Improve aptamer-ligand affinity by reselection of aptamers. 3) Develop riboswitches with alternative mechanisms (e.g. splicing regulation) and combine them with aptazyme-based riboswitches to improve the ON/OFF ratio.
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