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EXpanding Platforms for Efficacious mRNA Therapeutics

Periodic Reporting for period 1 - EXPERT (EXpanding Platforms for Efficacious mRNA Therapeutics)

Reporting period: 2019-09-01 to 2021-02-28

EXPERT is a timely, multidisciplinary 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
Progress during the 1st project period was affected by the COVID-19 pandemic, which led to lab closures for essentially all project partners. Despite that, we did achieve important insights into the factors that affect performance of our frontrunner mRNA formulation.
We have started to build a database on the standard operating procedures for experimental work, so that experiments are performed in the same way throughout the consortium, including for example the shipment and storage of the fragile mRNA molecules. We have also identified relevant variables that determine the efficacy and manufacturability of our mRNA nanoparticles. These insights were used in a screening effort to determine the activity of the lipid-based nanoparticles in vitro. Also, for more advanced emerging and exploratory carriers in vitro assays were performed. On the manufacturability front, we have tested different set-ups for the scaled-up production of our frontrunner formulation and developed assays to test the purity and stability of the individual components as well as the nanoparticle formulation. The lipid nanoparticles form the in vitro screen performed strikingly different in the in vivo setting which necessitates extra investments in the preclinical work to understand the structure-activity relationship.
Our frontrunner application is in oncology. The improved insight we obtain on the structure activity relationship between nanoparticle and functional delivery of the mRNA in the preclinical experiments will be of benefit for a large number of nucleic-acid based structures that also employ similar nanoformulations to deliver their therapeutic payload.
Within the consortium we have started work on an EU-developed proprietary ionizable lipid. The guidance provided by EXPERT on the critical factors for successful development of formulations with this lipid is applicable in many therapeutic areas. In sharp contrast to conventional small molecular weight drugs or proteins in drug development, where the structure and physicochemical characteristics of the compounds are different in every project, mRNA molecules have the same overall characteristics irrespective of their application. Only the sequence of the nucleotides differs. As a result, the knowledge obtained with our delivery materials has generic applicability for other nucleic acid therapeutics, especially the new ionizable lipids will strengthen the competitive position of European advanced therapy research and development. In addition, we have assembled emerging and exploratory carrier materials that have attractive properties for mRNA delivery. Together with the established ionizable lipid-based carriers we will build a comprehensive package of efficacy and safety data that has relevance for developers of nucleic acid-based therapeutics, regulators, and scientists in the field.