Periodic Reporting for period 4 - EXPERT (EXpanding Platforms for Efficacious mRNA Therapeutics)
Période du rapport: 2024-03-01 au 2025-02-28
The EXPERT consortium set out to overcome the principal bottlenecks limiting the clinical translation of mRNA therapeutics: functional tissue targeting, efficient cytosolic delivery, and immune tolerability. Over the course of the project, and particularly during the most recent reporting period, we have made substantial strides toward each of these goals. Through the development of novel biodegradable ionizable lipids and alternative delivery systems, we addressed delivery efficiency and flexibility. Our active contributions to international standardization efforts and the production of a GMP-ready high-concentration LNP batch mark significant progress toward regulatory and manufacturing readiness. The publication of an intratumorally active mRNA immunotherapeutic and the identification of a drug class that mitigates hypersensitivity reactions provide compelling proof-of-concept for both efficacy and safety. These achievements illustrate how EXPERT has delivered on its mission to create a scalable, off-the-shelf mRNA platform technology with direct therapeutic relevance—particularly in the field of cancer immunotherapy—and has laid a robust foundation for future clinical translation and industrial exploitation.
Following unexpected experimental results during the first reporting period, the EXPERT consortium strategically redesigned the project in the second phase to ensure maximum impact in the remaining runtime. The rationale behind this reset is explained in a video by the coordinator, available here: (https://www.expert-project.eu/user/pages/07.media/01._video/EXPERT_Interview_Clip_Preview.mp4(s’ouvre dans une nouvelle fenêtre))
Over the course of the project, we have made considerable progress in advancing the core objectives of EXPERT. Key achievements from the earlier phases include:
1. The development of a library of biodegradable ionizable lipids that enabled efficient mRNA delivery in vitro and in vivo.
2. The exploration of alternative delivery systems with distinct biological behavior.
3. Work on harmonizing quality control and pharmaceutical use of lipid nanoparticles and RNA therapeutics through ASTM and Europea Pharmacopoeia working groups
4. The initiation of a partnership development program with an EU-based global pharmaceutical company to advance EXPERT technologies toward translational application.
In the current reporting period, we have made a significant leap forward in terms of translational readiness and therapeutic potential.
Specifically, we:
• Produced a GMP-ready lipid nanoparticle (LNP) batch at high mRNA concentration, representing a major milestone for clinical and commercial applicability.
• Published a high-impact study on an intratumorally administered immunostimulatory mRNA cocktail, demonstrating potent activation of the local immune environment and underlining the clinical promise of our immune-targeted delivery strategy.
• Identified a class of small-molecule drugs capable of preventing hypersensitivity reactions associated with therapeutic nucleic acid-loaded LNPs. This discovery directly addresses a key safety concern in mRNA-based therapies and opens new avenues for co-treatment strategies or premedication protocols to improve patient tolerability.
Together, these achievements underscore the translational maturity of the EXPERT platform and its potential to deliver safe, scalable, and effective mRNA therapeutics. Dissemination of results has occurred through high-impact publications, conference presentations, and direct engagement with industrial stakeholders to facilitate future exploitation.
Over the course of the project, we have made considerable progress in advancing the core objectives of EXPERT. Key achievements from the earlier phases include:
1. The development of a library of biodegradable ionizable lipids that enabled efficient mRNA delivery in vitro and in vivo.
2. The exploration of alternative delivery systems with distinct biological behavior.
3. Work on harmonizing quality control and pharmaceutical use of lipid nanoparticles and RNA therapeutics through ASTM and Europea Pharmacopoeia working groups
4. The initiation of a partnership development program with an EU-based global pharmaceutical company to advance EXPERT technologies toward translational application.
In the current reporting period, we have made a significant leap forward in terms of translational readiness and therapeutic potential.
Specifically, we:
• Produced a GMP-ready lipid nanoparticle (LNP) batch at high mRNA concentration, representing a major milestone for clinical and commercial applicability.
• Published a high-impact study on an intratumorally administered immunostimulatory mRNA cocktail, demonstrating potent activation of the local immune environment and underlining the clinical promise of our immune-targeted delivery strategy.
• Identified a class of small-molecule drugs capable of preventing hypersensitivity reactions associated with therapeutic nucleic acid-loaded LNPs. This discovery directly addresses a key safety concern in mRNA-based therapies and opens new avenues for co-treatment strategies or premedication protocols to improve patient tolerability.
Together, these achievements underscore the translational maturity of the EXPERT platform and its potential to deliver safe, scalable, and effective mRNA therapeutics. Dissemination of results has occurred through high-impact publications, conference presentations, and direct engagement with industrial stakeholders to facilitate future exploitation.
Within the consortium we have worked extensively on the new EU-developed proprietary lipid class. It has shown attractive biological properties and the properties can be achieved at compositions that fall outside currently patented lipid nanoparticle formulations. This offers an opportunity for industrial exploitation as is exemplified by the new partnership.
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.
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.