Project description
Nature's intercellular couriers could soon be delivering powerful RNA therapies
Innovation has enabled numerous targeted therapies for myriad diseases and conditions. However, effective treatment can sometimes be hindered by complications in getting these therapies to their targets in vivo. RNA-based therapies are a case in point: their tremendous potential is curbed by inefficient means of delivery to diseased cells. And once again, the scientific community is turning to nature for a solution. Extracellular vesicles (EVs) are like intercellular couriers. These membrane-bound compartments carry cargo of biologically active molecules that can travel to local or distant targets to be unloaded in a highly specific way to execute defined biological functions. The EU-funded OBSERVE project is harnessing their power to deliver RNA therapies through enhanced understanding of the mechanisms of loading, delivery, uptake and intracellular trafficking.
Objective
RNA-based therapeutics, including siRNA, miRNA, mRNA and CRISPR/Cas9 components, have unprecedented therapeutic potential and hold the promise of treating any disease with a genetic component. However, inefficient delivery into diseased cells hinders their clinical progress. Consequently, there is an urgent need for novel, original approaches to overcome the delivery challenges.
Recently, an endogenous RNA transport system has emerged, based on the release and uptake of extracellular vesicles (EVs). EVs are naturally equipped to transfer RNA molecules to other cells in a functional and selective manner. Furthermore, I have recently demonstrated that EVs deliver RNA more efficiently than state-of-the-art synthetic RNA nanocarriers. Thus, EVs hold promise as a new paradigm for RNA delivery. However, the mechanisms underlying EV-mediated RNA transfer are unknown, and reproducible methods for efficient loading of EVs with therapeutic RNA are lacking.
The aim of my proposal is to (1) elucidate the mechanisms underlying EV internalization and processing that lead to the functional delivery of their RNA content and (2) radically improve the loading efficiency of EVs for therapeutic RNA delivery. To realize this, I will:
1) Identify genes and pathways involved in EV-mediated RNA transfer using a novel CRISPR/Cas9-based RNA delivery reporter system.
2) Systematically compare uptake and intracellular trafficking of EVs and synthetic nanocarriers.
3) Design a novel and improved method to load EVs with therapeutic RNA.
4) Demonstrate the effect of EV-mediated delivery of therapeutic RNA in a murine model of myocardial infarction.
The outcome of this research will fundamentally advance our understanding of the cellular processes enabling EV-mediated RNA transfer, which is of crucial importance for the development of EV-based and EV-inspired delivery systems. This research will accelerate clinical translation of an entire new class of therapeutics based on EVs and RNA.
Fields of science
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Funding Scheme
ERC-STG - Starting GrantHost institution
3584 CX Utrecht
Netherlands