Development of “smart” amplifiers of reactive oxygen species specific to aberrant polymorphonuclear neutrophils for treatment of inflammatory and autoimmune diseases, cancer and myeloablation.

Informations projet

NeutroCure

N° de convention de subvention: 861878

DOI

10.3030/861878

Projet clôturé

Date de signature de la CE 30 Août 2019

Date de début 1 Janvier 2020

Date de fin 31 Octobre 2025

Financé au titre de

• EXCELLENT SCIENCE - Future and Emerging Technologies (FET)

Coût total

€ 2 999 998,75

Contribution de l’UE

€ 2 999 998,75

Coordonné par

FRIEDRICH-ALEXANDER-UNIVERSITAET ERLANGEN-NUERNBERG
Germany

Periodic Reporting for period 3 - NeutroCure (Development of “smart” amplifiers of reactive oxygen species specific to aberrant polymorphonuclear neutrophils for treatment of inflammatory and autoimmune diseases, cancer and myeloablation.)

Période du rapport: 2022-11-01 au 2023-08-31

Résumé du contexte et des objectifs généraux du projet

NeutroCure goal is to develop improved drugs for an effective immune system. An over-active immune system may lead to chronic inflammation and the cytokine storm phenomenon that can be observed during infection. Our hypothesis is that resolution of inflammation is dependent on the timely production of reactive oxygen species (ROS) by the first inflammatory cell on the scene, the neutrophil, to maximize clearance of pro-inflammatory debris. We know that if ROS production is insufficient, for example when the enzyme NOX2 is absent or mutant, then inflammation persists. Central to our project is the development of new technology to resolve inflammation - novel ROS-amplifiers that are designed as single- and multiple-trigger-dependent prodrugs targeting different organelles within cells. As triggers we use elevated ROS, extracellular DNA in NETs and peroxidases as well as their combinations. Two classes of prodrugs are being designed, synthesized, formulated and evaluated during the project. The first class of these acts independently of NOX2 and is based on various Fe(II) complexes (including N-alkylaminoferrocenes (NAAF), clathorchelates). The second class is NOX2-dependent, organic drugs.

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

Within the first reporting period (01.01 – 31.12.2020) we have synthesized and evaluated first prototypes of unspecific NOX2-dependent and independent ROS amplifiers. We optimized their synthesis. Based on these data, we produced first prototypes of neutrophil elastase- and ROS-dependent ROS amplifiers. Furthermore, we set-up assays to assess ROS-production, NET formation and killing of cancer cells mediated by neutrophils.
Within the second reporting period (01.01.2021 - 31.10.2022) we have synthesized and evaluated in vitro and in vivo effects of multiply-triggered ROS amplifiers. We scaled up the synthesis of the selected prodrugs and obtained them in quantities sufficient for the following in vivo studies using advanced murine models.
Within the third reporting period (01.11.2022 - 31.08.2023) we have finalized (a) the selection of the prodrugs for their further pre-clinical and clinical development; (b) selection of an indication, for which these drugs will be used - CGD; (c) set-up the plan for further development of the prodrugs.

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)

NeutroCure (cooperation of FAU, LNMU and UKER) has developed ER-specific ROS-amplifier targeting ROS-rich cells, e.g. cancer cells. The functionality of this prodrug was confirmed in cell free settings, in cells and in vivo. It can potentially find applications in cancer treatment. Reference: doi.org/10.1002/anie.202100054.

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