Structure Based Design of RNA Therapeutics
Introduction
RNA therapeutics are emerging as a new way of targeting previously un-druggable therapeutic targets and their full potential has yet to be realized. The focus has been on RNA sequence, whereas next-generation therapies will also utilize RNA structure. Current mRNA therapy design requires optimization of 5’ and 3’ UTRs as well as the coding sequence to maximize the translational output of mRNA. UTRs regulate the translation and degradation of mRNA. However, a key property of 5’ and 3’ UTRs is their complex 3D structure that allows them to regulate protein expression in a tightly controlled manner. Currently, 5’ and 3’ UTR sequences for mRNA therapeutics are borrowed from naturally occurring sequences that have abundant translational output, resulting in an mRNA therapeutic that is ubiquitously expressed wherever the mRNA encounters translational machinery. Harnessing the full regulatory power of 5’ and 3’ UTRs for translational control of mRNA therapeutics would allow for expression of the mRNA payload only in the correct cellular context and reduce off-target effects. We aim to exploit the cancer cell environment to enable cell state-specific expression and stabilization of the mRNA therapy in the presence of proteins known to be overexpressed in cancers.
Methods
We will use a combination of in silico structural design, cryo-EM characterization, and in vitro assays to assess the effects of UTR elements in the translational regulation of a reporter construct in cancer cell line models.
Results
We anticipate to get preliminary results by October 2023 and final results by August 2024.
Conclusion
This is a new project; no conclusions to date.