Many of the cellular functions are carried out by proteins. mRNA therapeutics are man-made molecules which - when introduced into cells - act as a blueprint to make these proteins. Virtually any protein of choice can be made using this technique, but the current methods to predesignate which cell type will make the protein are very limited. Hence, we cannot control which cells will make the protein after mRNA therapeutics are injected in the blood stream. This project aims to develop additional pieces of mRNA code which can be added to the protein code. These new components ensure that the therapeutic protein can only be made by targeted cell types and not by other cells. More specifically, this project aims to selectively produce toxic proteins in lung cancer cells while avoiding adverse effects on healthy cells.
Messenger RNA (mRNA) transfers the genetic sequence of a gene from the nucleus to the cytosol. There, mRNA is translated into functional proteins after which it is quickly degraded. Current technologies have raised mRNA from an unstable intermediary to a potential game changer in modern medicine. Indeed, introducing mRNA therapeutics into any given cell leads to immediate production of the encoded therapeutic protein. Moreover, recent developments in nanomedicine now allow mRNA encapsulation in lipid nanoparticles (LNPs) to achieve safe and broad tissue distribution in humans . However, targeted delivery of these mRNA-LNPs to a specific pathological site in the body remains a currently unaddressed obstacle in leveraging this technology to full-scale clinical use . “TaSeTra” (Targeting by Selective Translation) is the key concept of this proposal and uses stable mRNA stem-loop structures to restrict translation of mRNA therapeutics to a targeted cell type (Figure 1). This introduces the novel concept of transferring the targeting function from the nanocarrier to the drug (mRNA) payload, thereby bearing the potential to achieve a breakthrough in the field. This proposal intends to develop TaSeTra-based mRNA therapeutics nanoformulated in LNPs and assess their lung tumor targeting potential. Such interdisciplinary research combines high throughput mRNA design with development of RNA nanocarriers at SINTEF (Trondheim). In addition, the proposal is supported by expertise in lung cancer models at Antonio Maraver’s group (Montpellier Cancer Research Institute, IRCM). The proposed research builds upon a Young Investigator Proof of Concept startup grant obtained at the Cancer Research Institute Ghent (Belgium) and fits within the framework of “TheRNApy”, SINTEF’s strategic project which explores commercial opportunities in the field of mRNA therapeutics.