Cardiac regeneration by mRNA-triggered proliferation of cardiomyocytes

Projektinformationen

REGeRNA

ID Finanzhilfevereinbarung: 101057318

DOI

10.3030/101057318

EK-Unterschriftsdatum 18 Mai 2022

Startdatum 1 September 2022

Enddatum 31 August 2027

Finanziert unter

• Health

Gesamtkosten

€ 5 010 638,75

EU-Beitrag

€ 5 010 638,00

Koordiniert durch

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 2 - REGeRNA (Cardiac regeneration by mRNA-triggered proliferation of cardiomyocytes)

Berichtszeitraum: 2024-03-01 bis 2025-08-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Heart failure is recognized as a major health problem worldwide both in terms of patient management and related costs. Its main underlying origin is the loss of millions of functional cardiomyocytes. Even though several treatments improve heart function and clinical outcomes, they all fail to address this root cause. Replacing the lost cardiomyocytes with new contractile cells is a real challenge because, unlike many non-mammalian species, the adult human heart does not regenerate spontaneously. An option that emerged over the last two decades to replenish the pool of functional cardiomyocytes is cell therapy, based on the premise that the exogenously transplanted cells would engraft in the recipient myocardium and couple with their host counterparts to make a functionally effective myocardial syncytium. Overall, the outcomes of most trials have been disappointing, and despite occasional hints of efficacy, few have conclusively demonstrated stable and durable cardiomyocyte engraftment and clear evidence of true myocardial ‘regeneration’.
The main objective of the REGeRNA project is thus to develop a synthetic messenger RiboNucleic Acid (mRNA) able to trigger the proliferation of endogenous (quiescent) cardiomyocytes and functionalized in such a way that the product is functional in cardiomyocytes only, thereby minimizing cellular off-target deleterious effects. This construct should be conveyed to the heart via lipid nanoparticles (LNP), either by direct myocardial administration or systemically following LNP engineering with cardiac-specific receptors enabling their selective targeting to the heart.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

The REGeRNA Project started in September 2022, putting together 6 partners from 5 European countries. The project is progressing well towards its objectives.

A lead mRNA product has been identified after an extensive screening of putative factors. It is called CPY, is a single linear bicistronic mRNA coding for Cyclin D2 and YAP5SA, and it induced proliferation in vitro in cardiomyocytes, not in cardiac fibroblasts. However, in a mouse model of myocardial ischemia/reperfusion, the first set of experiments has shown that its inclusion in LNPs failed to improve function following its direct intramyocardial injections or to induce cell proliferation (regardless of cell phenotype). The assessment of fibrosis (work in progress) will be critical to confirm that at least CPY does not increase fibroblast proliferation, thereby justifying to skip engineering the mRNA with microRNAs allowing a cardiomyocyte-specific expression (as originally planned), a task which has shown to be challenging despite the careful adherence to a published protocol impossible to reproduce.

Interestingly, however, parallel biodistribution experiments performed over the reporting period and entailing the similar intramyocardial injections of either LNP or a naked mRNA, both shuttling a fluorescent reporter, have shown equivalent signals in the heart, thereby paving the way for a next set of injections of mRNA alone (only encapsulated in a polymer intended to optimize transfection of the cardiac cells).

In parallel, different LNP formulations modified to reduce liver targeting and increase cardiac homing have been performed but have not yet allowed systemic delivery to enable a substantial delivery of the vectors in heart tissue; studies on these formulations are continuing.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

The project could have a major impact on the management of severe heart failure by allowing a partial restoration of a contractile cell pool through the re-induction of tissue-resident cardiomyocyte proliferation or even their re-entry in a cell cycle leading to polyploidy or multinucleation, even without a final exit towards cytokinesis. In parallel, the development of a LNP formulation de-targeting the liver (and in our case, allowing a substantial cardiac homing), would benefit the overall field of organ targeting of intravenously delivered therapeutics. Namely, while some features of the LNP formulation could be generically used for mitigating phagocytic events in the liver, the nature of the LNP-anchored binder could allow to specifically target a given organ depending on the disease under consideration.

A web site has been developed (https://www.regerna.eu//) and regularly updated with all the information relevant to the project.

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