mRNA sequence engineering and uses thereof
Maximized mRNA lifespan and translation for mRNA-based therapy applications.
Many diseases emerge from irregularities that occur during protein synthesis. While limited therapies exist to deliver mature proteins to compensate for these errors, protein therapy by direct protein delivery has limited efficiency. This is due to difficulty in controlling the volume of delivered protein as the therapeutic protein is often metabolized or degraded before reaching the target tissues. As an alternative to protein therapy, mRNA-based therapy using in vitro transcription (IVT) is an emergent therapeutic field. In mRNA-based therapies, protein-coding mRNA is synthesized in the laboratory and these transcripts are introduced into cells where the host machinery translates transcripts into mature proteins.
However, after delivery of the mRNA to the cell, the delivered mRNAs have extremely variable translation rates. Therefore, there is a need to improve the rate of protein expression and extend the lifespan of delivered mRNAs. Attempts to maximize translation and lifespan of delivered mRNA for therapeutic applications have largely focused on engineering the mRNA poly(A) tail. However, while engineered poly(A) tails have had demonstrable success in increasing lifespan and translation, this method is unreliable due to inherent obstacles. For example, the standard method of storing DNA plasmid vectors that are the source of therapeutic mRNA often removes these engineered features prior to any attempt to deliver the mRNA. Therefore, there is a need to develop a reliable method for stabilizing lifespan and translation efficiency of therapeutic mRNAs that leads to stable expression rates for the development of consistent and effective protein therapies.
Researchers at the Ohio State University led by Yizhou Dong have developed a method to maximize mRNA lifespan and translation using a set of engineered mRNA compositions. These mRNA compositions have engineered regulatory sequences that do not affect the structure and function of the translated protein. Rather, these regulatory sequences affect the manner in which mRNA interacts with the translation machinery of the cell. Employing these sequences improves upon previous attempts to enhance mRNA lifespan and translation efficiency because the method thereby avoids the inherent pitfalls of previous methods by exploiting a new mechanism. Therefore, this method of engineering mRNA regulatory sequences is an important new method for designing mRNA to be used for protein therapy, and could improve the feasibility of all mRNA-based protein therapy.