THERAPEUTIC EPIGENETIC ENHANCEMENT OF THE INNATE IMMUNITY TO EFFECTIVELY COMBAT ANTIMICROBIAL RESISTANCE [IN-ARMOR]

Informations projet

IN-ARMOR

N° de convention de subvention: 101080889

DOI

10.3030/101080889

Date de signature de la CE 15 Mars 2023

Date de début 1 Mai 2023

Date de fin 30 Avril 2027

Financé au titre de

• Health

Coût total

€ 5 998 972,50

Contribution de l’UE

€ 5 998 972,25

Coordonné par

HASKOLI ISLANDS
Iceland

Periodic Reporting for period 1 - IN-ARMOR (THERAPEUTIC EPIGENETIC ENHANCEMENT OF THE INNATE IMMUNITY TO EFFECTIVELY COMBAT ANTIMICROBIAL RESISTANCE [IN-ARMOR])

Période du rapport: 2023-05-01 au 2024-10-31

Résumé du contexte et des objectifs généraux du projet

Antimicrobial resistance (AMR) and multi-drug resistance, where pathogens evolve to resist antibiotics, are recognized by the WHO as top global health threats, linked to 4.95 million deaths in 2019. The rise of multi-drug or pan-drug resistant strains could trigger the next global pandemic. Current treatments are costly, slow to develop, and face resistance risks. Innate immunity offers a promising solution by producing antimicrobial molecules, peptides, and proteins that directly inhibit bacteria, viruses, fungi, and protozoa. Small molecules, known as Immune System Inducers (ISIs), can stimulate this natural defense mechanism. Building on this concept, IN-ARMOR brings together experts from 9 universities, research institutes, and 7 medical and industry partners across 9 EU countries. The project aims to develop a new class of ISI-based therapies to combat AMR and target the 13 most dangerous infections, including two priority-1 pathogens. IN-ARMOR focuses on inflammatory bowel disease (IBD) and gastrointestinal (GI) infections as initial targets. Novel compounds will be developed using in-silico methods and advanced nanotechnology-based drug delivery systems. The therapies will undergo preclinical validation for safety and efficacy, both in vitro and in vivo, to meet investigational medicinal product requirements.

Upon completion, IN-ARMOR will be prepared for clinical validation. Upon commercialization, IN-ARMOR could potentially save more than 4 million lives worldwide and result in the significant burden reduction of antibiotic development with long-term cost reduction impact of € 107 billion, whilst reducing the global disease burden by 96.84 million DALYs (disability-adjusted life years).

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

Work Package 1 successfully met its objectives by designing, synthesizing, and characterizing over 100 novel compounds called Immune System Inducers (ISIs). Structural characterization and purity determination were completed for these compounds, and sufficient quantities were distributed to project partners for high-throughput screening (HTS) and in vitro studies. The HTS assays evaluated the compounds’ ability to induce the CAMP gene (a biomarker for innate immunity) and inhibit HDACs, with the results guiding the design of subsequent compound iterations and the final selection of lead candidates. Kinetic solubility tests were also performed to support the identification of lead candidates. A computational AMES test confirmed the non-mutagenicity of a key compound. Lastly, chemical probes with specialized functional groups were synthesized to facilitate downstream studies of compound interactions, preparing the basis for target identification of ISI compounds in WP2.

Progress in Work Package 2 has focused on narrowing down the selection of lead compounds to 20, based on their CAMP-induction profiles, ability to restore tight junction integrity, antimicrobial activity, and low cytotoxicity. Ongoing work includes studying the compounds in cell infection models using human macrophages and epithelial cell lines, evaluating their effects on bacterial infections, and using a proteomics-based approach for untargeted analysis of ISI´s downstream effects. Stability studies for these compounds are also in progress.

Work Package 5 focuses on regulatory activities and Health Technology Assessment (HTA) to support the development and evaluation of the project’s outcomes. An Innovation Task Force meeting with the European Medicines Agency was organized, providing critical discussions on scientific and regulatory strategies for the project. Additionally, a systematic review on the cost-effectiveness of immunotherapies for GI diseases was completed and registered with PROSPERO (an international database for registering systematic reviews in health and social care). Preparations for the HTA report began, including the definition of the HTA framework and health-economic evaluation study protocol. This work aligns with EU HTA Regulation 2021/2282 and will assess the societal and economic impacts of project technologies.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

1. Targeting Innate Immunity, Not Pathogens
IN-ARMOR uses ISIs to stimulate HDPs like cathelicidin and defensins. These peptides kill pathogens and activate immune cells, creating a multifaceted immune response. This reduces the risk of resistance, as pathogens struggle to adapt to multiple defenses.

2. Selective Impact on Pathogens
Unlike broad-spectrum antibiotics that disrupt gut microbiota, ISI compounds selectively boost defenses against harmful pathogens while preserving microbial diversity, promoting gut health and preventing dysbiosis.

3. Prophylactic and Therapeutic Applications
ISI’s compounds work both as a preventive solution and treatment, reducing infection risks during surgeries or chemotherapy, tackling AMR proactively.

4. Nano-Encapsulation for Drug Delivery
Advanced nano-encapsulation ensures precise delivery of ISI compounds to GI tissues, enhancing stability and preventing premature degradation.

5. Global Impact and Transformative Outcomes
By enhancing innate immunity, IN-ARMOR provides a scalable and cost-effective solution. It could reduce AMR-related deaths by 78%, save 4 million lives globally, and cut healthcare costs by €107 billion. The therapy aims to improve the quality of life for 143 million EU citizens with GI diseases and reduce the global disease burden by 96.84 million disability-adjusted life years (DALYs).

6. Facilitating Future Innovation
IN-ARMOR will establish in vitro and in vivo models and clinical safety guidelines, creating a foundation for future immunotherapies and accelerating responses to emerging infectious diseases.

Comparison of Conventional Antibiotic Approach vs. In-Armor's Host-Directed Therapy in Combating AMR