Targeting the epigenome: towards a better understanding of disease pathogenesis and novel therapeutic strategies in Multiple Sclerosis

Informations projet

Epi4MS

N° de convention de subvention: 818170

DOI

10.3030/818170

Projet clôturé

Date de signature de la CE 14 Février 2019

Date de début 1 Juin 2019

Date de fin 31 Decembre 2025

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 1 998 798,00

Contribution de l’UE

€ 1 998 798,00

Coordonné par

KAROLINSKA INSTITUTET
Sweden

Periodic Reporting for period 4 - Epi4MS (Targeting the epigenome: towards a better understanding of disease pathogenesis and novel therapeutic strategies in Multiple Sclerosis)

Période du rapport: 2023-12-01 au 2025-05-31

Résumé du contexte et des objectifs généraux du projet

Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system and a leading cause of incurable progressive disability, including physical, cognitive impairment and fatigue, among young adults in Europe. Current treatments act broadly on the immune system and are associated with serious safety concerns. Although the exact cause remains unknown, this immune-mediated disease is likely triggered by environmental factors in genetically predisposed individuals. I proposed that epigenetic mechanisms, which regulate gene expression without affecting the genetic code, mediate the processes that cause MS and that aberrant epigenetic states can be corrected towards recovery. The overall goal of Epi4MS project is thus to empower translational MS research by facilitating better understanding of still largely unknown disease mechanisms and providing basis for more precise therapeutics. Improved MS management will in turn have a significant impact on the European society that carries the burden of extremely high and ever-increasing costs of medicines, assistance and absence from the work force of people suffering from MS. Epi4MS exploits the stable and reversible nature of epigenetic marks, in particular DNA methylation, to gain insights into the novel modifiable disease mechanisms, and is organized around three synergistic facets aiming to: (i) identify epigenetic states that characterize the pathogenesis of MS, (ii) prioritize functional epigenetic states using high-throughput epigenome-screens, and (iii) develop novel approaches for precision medicine based on correcting aberrant epigenetic states. We are utilizing unique biosamples combined with cutting-edge methodologies to capture pathogenic cells and measure their functional states and their MS target proxies. We are complementing these analyses with studies of the functional impact of MS targets using innovative in vitro screens, with the added value of unbiased discovery of regulators of important MS pathways. Finally, we are utilizing our extensive experience with animal models to dissect molecular mechanisms and test the therapeutic potential of targeted epigenome editing in vivo. Our findings aim to set the stage for a paradigm-shift in studying and treating chronic inflammatory diseases based on preventing and modulating aggressive immune responses by inducing self-sustained reversal of aberrant epigenetic states.

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

The progress of Epi4MS is summarized around the three synergistic aims of the project.
(i) Identification of epigenetic states that characterize the pathogenesis of MS. We made progress on three interconnected fronts, including (i) deeper characterization of the pathogenic cells that trigger MS, utilizing multiple omics and single-cell analysis in unique MS biosamples; (ii) epigenomic and transcriptomic states that associate with the MS state or response to MS treatment, focusing on genome-wide analysis of biosamples enriched in pathogenic cells, such as cells from cerebrospinal fluid as well as clones with pathogenic features from peripheral blood; and (iii) molecular and analytical methods development to achieve better quantification of DNA modifications and non-coding RNAs specifically, as well as to improve their functional annotation.
(ii) Prioritization of functional epigenetic states using high-throughput epigenome-screens. This aim is grounded in the ability to induce specific epigenetic changes. To that end, we have designed, evaluated and optimized, with respect to the nature of the epigenetic modification, stability and on-target vs. off-target effects, a set of novel and available molecular tools for the CRISPR-based sequence-specific deposition of epigenetic marks. These findings now guide selection of the tool depending on the application. We have also generated two reporter cell lines, modeling cellular functions of interest in the MS pathogenesis. These lines stably express epigenome-editing constructs and are ready for functional screens following transduction with guide RNA libraries that are currently under construction.
(iii) Development of novel approaches for precision medicine based on correcting causal epigenetic states. We have established MS model that better mimics disease progression and we are continuously testing and improving methods for delivery of drugs and epigenome-editing tools based on nanoformulations and viral carriers. Epi4MS has generated inducible conditional-ready transgenic mouse line, currently under characterization, expressing one of the epigenome-editing constructs developed in (ii) as a model to study the functional impact and therapeutic potential of epigenome-editing.
In the next stage, Epi4MS will focus on consolidating the epigenetic profile of pathogenic cells, by finalizing analyses in MS cohorts in combination with epigenome-screens, and validating the functional impact and therapeutic potential of targeting most critical states.

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)

The exact cause of MS is unknown and molecular and cellular mechanisms of disease are still largely undefined, translating into our limited ability to prevent, cure or even effectively treat MS. Thus, the overarching goal of Epi4MS is not only to identify molecular causes of chronic inflammatory diseases such as MS but to go beyond by developing alternative modalities for precision medicine based on discovering and correcting modifiable aberrant epigenetic states. This will be achieved by our multifaceted approach, built on cutting-edge molecular and analytical tools, to study processes in affected human tissue followed by functional validation in experimental models, supported by the progress achieved thus far. Epi4MS will provide novel insights, already emerging from conducted studies, into the MS pathogenesis based on characterizing epigenetic states of pathogenic cells and focusing on the converging targets across multiple approaches to capture cellular MS culprits. This will significantly improve our understanding of disease pathogenesis as well as the mechanisms underlying the most potent MS drugs, opening up possibilities for further studies of pathogenic cells and importantly, provide candidates for new therapeutic interventions. Importantly, Epi4MS will develop strategies and tools to validate the functional impact of disease-associated epigenetic changes, in the form of emerging molecular tools, screens and in vivo models, thus uncovering regulatory states warranting further investigations. This facet will also provide valuable tools for high-throughput identification of methylation-sensitive regulatory elements, which will have applications in numerous conditions that associate with immune cell biology in general. Ultimately, Epi4MS will establish complementary approaches to functionally validate epigenetic changes and address their therapeutic potential in vivo, setting the stage for the development of alternative therapeutic modalities based on correcting aberrant epigenetic states.

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