EXpanding Platforms for Efficacious mRNA Therapeutics

Project Information

EXPERT

Grant agreement ID: 825828

DOI 10.3030/825828

EC signature date 3 July 2019

Start date 1 September 2019

End date 28 February 2025

Funded under

• SOCIETAL CHALLENGES - Health, demographic change and well-being

Total cost € 15 010 087,50

EU contribution € 14 931 337,50

Coordinated by

UNIVERSITAIR MEDISCH CENTRUM UTRECHT
Netherlands

Periodic Reporting for period 2 - EXPERT (EXpanding Platforms for Efficacious mRNA Therapeutics)

Reporting period: 2021-03-01 to 2022-08-31

Summary of the context and overall objectives of the project

EXPERT is a consortium that is assembled to deliver mRNA therapeutics. mRNAs are molecules that encode proteins. The sequence of the building blocks of an mRNA determines the structure of the protein that is produced using the mRNA as a template. By adapting the sequence of the mRNA-building blocks any protein of interest can be made. As a result, successful delivery of an mRNA offers a new way of therapeutic intervention by making a protein that is effective in curing the disease. This makes mRNA an ideal candidate for platform development, as is exemplified by several of the COVID-19 vaccines, where production of the spike protein after vaccination leads to a highly efficient immune response. The main challenge to develop this platform is the safe and efficient target cell delivery to ensure performance. Therefore, we aim to develop an effective off-the-shelf platform-based nanosized delivery system for mRNA.

Our frontrunner application is based on activating the immune system to eradicate cancer. The field has up to now witnessed exciting clinical data in some selected applications underlining proof-of-concept. For example, ex vivo mRNA transfection of dendritic cells provided remarkable therapeutic benefit in advanced melanoma patients. These results were accomplished by one of our industrial consortium partners. Still, it does not take advantage of the promise of mRNA to be an off-the-shelf platform product, which would strongly boost the therapeutic impact.
This example motivates EXPERT partners to build innovative nanomedicine-platforms that tackle the bottlenecks for widespread therapeutic mRNA application.
EXPERT will address three major research goals that have limited mRNA therapy from displaying its full potential:
1. The ability to achieve functional target tissue delivery of mRNA by nanomedicine design
2. The capacity to efficiently reach target cell cytoplasm, the site of mRNA activity
3. The capability to circumvent adverse immune responses towards mRNA nanomedicines

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Following unexpected experimental results in the first period, the EXPERT consortium redesigned the project in the second period. The rationale for his reset has been explained in a video by the coordinator (https://www.expert-project.eu/user/pages/07.media/01._video/EXPERT_Interview_Clip_Preview.mp4 ). The redesigned work plan is aimed to provide maximum impact in the remaining runtime of the project.
In this second period, we have identified a new class of lipids that forms an integral part of the new lipid nanoparticles that show attractive biological properties. These will be our frontrunner modalities. We are assembling flanking technologies for their scalable and reproducible manufacture and provide technologies to measure their quality. Also, emerging and exploratory carriers show different biological behavior that we are trying to exploit in specific settings.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Within the consortium, we have worked extensively on the new EU-developed proprietary lipid class. It has shown attractive biological properties and these properties can be achieved at compositions that fall outside currently patented lipid nanoparticle formulations. This offers an opportunity for industrial exploitation.
The guidance provided by EXPERT on the critical factors for successful development of formulations with this lipid is applicable in many therapeutic areas. This knowledge will benefit the new ionizable lipids and will strengthen the competitive position of European advanced therapy research and development.
For the emerging and exploratory carrier materials we have seen interesting biological performance. These could be exploited in specific disease indications. A surprising finding was that exploratory carriers could outperform the current state-of-the-art materials 1000-fold. This means that there is a clear opportunity to learn form these systems and transfer attractive properties to the established materials.
Together we are building a portfolio, where we expect the frontrunner established lipid nanoparticles to be ready for clinical trials whereas other materials have contributed to new design ideas that fill the pipeline for selected applications.

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