Award details

Inspired by nature: Exosomes as RNA delivery platforms

Reference	BB/M024393/1
Principal Investigator / Supervisor	Professor Matthew Wood
Co-Investigators / Co-Supervisors	Dr Samir El-Andaloussi
Institution	University of Oxford
Department	Physiology Anatomy and Genetics
Funding type	Research
Value (£)	412,223
Status	Completed
Type	Research Grant
Start date	01/10/2015
End date	31/03/2019
Duration	42 months

Abstract

Silencing of target gene expression through RNA interference (RNAi) has unprecedented therapeutic potential, however inefficient intracellular delivery of the RNAi-mediating small RNA molecules hinders its clinical progress. Consequently, there is a need for novel, original approaches to overcome the delivery challenges. Most recently, an endogenous RNA transport system has emerged, based on the release and uptake of extracellular vesicles (exosomes). We and others have shown that exosomes are capable of transferring RNA molecules to other cells, thereby influencing the function(s) of the recipient cell. This suggests that exosomes utilize native mechanisms for cellular internalisation and trafficking and raises the possibility of utilising exosomes as vehicles for therapeutic RNA delivery. The aim of this proposal is to identify essential exosome components that contribute to exosome cell targeting and internalisation leading to functional delivery of their RNA content. To realise this, exosomes with different composition and properties will be prepared by varying the culture conditions of cells from which exosomes are derived. Exosomes will then be loaded with small RNA molecules and evaluated for their uptake and RNA delivery efficiency. Exosomes with increased or decreased uptake and/or silencing efficiency will be fully characterised using proteomics and lipidomics approaches, and the direct contribution of candidate exosomal proteins or lipids to exosome uptake and delivery will be evaluated. Finally, as a proof-of-principle, we will incorporate the newly discovered exosome features into liposomes and evaluate liposome uptake and delivery efficiency. This work will increase our comprehensive understanding of the natural RNA delivery mechanisms of exosomes, which helps to optimise exosome-based drug delivery systems. In addition, it will provide new opportunities for improvement of current synthetic systems through exosome-inspired engineering.

Summary

RNA interference (RNAi) is a highly promising method to switch off the activity of virtually any disease-causing gene. It therefore has enormous therapeutic potential. The process of RNAi is carried out by small pieces of RNA (an information carrying molecular similar to DNA), which must be taken up into the cells of the body in which the disease-causing gene is active. Because of the size and nature of these small RNAs (which are much, much larger than typical drugs such as for example paracetamol), this step of cell delivery has proven to be a major challenge and remains the critical obstacle hindering the clinical progress of RNAi. Most recently and very surprisingly, it has been discovered that in the human body a natural transport system exists that is capable of transferring naturally occurring small RNAs between cells. This transport system consists of extremely tiny particles surrounded by a fatty membrane, called exosomes. In this project, we now plan to take a leaf from nature's book and study this natural communication system embodied by exosomes, in order to either utilise it to deliver small pieces of RNA for therapeutic purposes, or to use the knowledge gained from understanding how exosomes work to design exosome-inspired synthetic methods for RNA delivery.

Impact Summary

This project aims to identify exosome components that contribute to exosome cell targeting and internalisation leading to functional delivery of their RNA content. Our expertise coupled with the tractability and novelty of the experimental paradigms proposed, means that this project has a very high chance of establishing important new knowledge. We therefore envisage a series of major impact pathways from this project generated by the academic team conducting the work, including publication of our findings, wider communication of their significance and finally application and exploitation of our results. Project impacts relate to successfully undertaking science of the very highest quality, communicating the results of this to scientific and wider public audiences and capitalising on the scientific findings through novel intellectual property, where possible, to allow exploitation. The project team will be led by Wood (Oxford), who is a highly experienced leader of major international projects (e.g. Wellcome Trust / Department of Health HICF, EU Innovative Medicines Initiative) leading in timely fashion to highly successful outcomes and impacts. Wood and EL Andaloussi will meet regularly as a management group to coordinate the project activities and priorities, progression to timelines and milestones and to ensure that outcomes and impact are maximised as outlined below. Scientific communication of project progress and scientific data will be led by Wood and EL Andaloussi via the well-established channels of presentation at national and international scientific conferences and peer review publication. Data will be shared with the research community in timely fashion as outlined in the data management plan, principally via peer review publication and depositing large datasets in public repositories. More general communication and wider public engagement will be centred on departmental websites and interactive media on web and mobile platforms to communicate the overall objectives of the project and on-going progress and findings of the project. Wider public communication including a schools programme will be facilitated by the Medical Sciences Division Public Engagement team at the University of Oxford, through well-established links with local and regional schools and via Oxford science days held termly or annually in Oxford. With regard to impacts related to application and exploitation, it is highly likely that a more detailed understanding of the biology underlying exosome-mediated communication between cells will lead to a number of potentially important impacts: - Development of exosome-inspired synthetic RNA delivery systems. - Interfering with exosome transport, uptake or signalling could be novel strategies to inhibit disease progression All intellectual property will be managed by Isis Innovation, the technology transfer company of the University of Oxford, who will assess, protect and commercialise the IP generated from the project.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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