Kenneth Loi Rose Hills
Investigating Modified mRNA Stability and Translational Fidelity
mRNA has proven to be a promising novel therapeutic class due to its programmability, low barriers to synthesis, and rapid translation into protein in vivo. mRNA as a platform technology has led to the development of broad applications such as vaccines, therapeutic protein replacement, in vivo genome editing, and in vivo cellular reprogramming. Despite growing interest in mRNAs therapeutic potential, it suffers from low delivery rates due to its instability and short half-life, thereby limiting its clinical adoption. mRNA transcripts are vulnerable to various degradation mechanisms in the cell, as well as self-catalyzed cleavage. The proposed project aims to identify chemically modified nucleotides that can be incorporated into mRNA using in vitro transcription. The modified transcripts will subsequently be characterized by their stability as well as translational fidelity. Stabler versions of modified mRNA with similar or even greater translational efficiency would help alleviate bottlenecks in therapeutic delivery, thereby conferring near-term benefits such as improved mRNA-based vaccine efficacy. This body of work explores nucleic acids biochemistry for foundational development of improved mRNA technologies.