Cardiac regeneration by mRNA-triggered proliferation of cardiomyocytes

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Research unit

SERI

Project number

22.00266

Project title

Cardiac regeneration by mRNA-triggered proliferation of cardiomyocytes

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Abstract (English)	Heart failure (HF) is a major health problem worldwide because of the high number of patients and the related costs. Current treatments are not consistently efficacious and fail to address the major underlying cause of HF: the massive loss of cardiomyocytes in damaged regions. REGeRNA has been designed to address this issue by leveraging advances in synthetic mRNAs and their lipid nanoparticle (LNP)-based carriers to generate a construct able to reactivate mechanisms mediating cardiomyocyte proliferation in development but which are shut-down shortly after birth. REGeRNA is organised in 6 work packages that follow a roadmap towards endogenous heart repair. The program starts tailoring various human assays and in vitro models such that they can reliably document cardiomyocyte proliferation. These will then be used for screening pathways thought to be involved in cardiomyocyte division, among which Hippo is our primary candidate. mRNA(s) encoding the relevant proteins will be subsequently synthesised and engineered such that their expression is restricted to cardiomyocytes and no stromal cell expansion occurs. An LNP formulation will then be developed for incorporation of the synthesized mRNA(s) and optimized for cardiomyocyte-specific delivery. Subsequently, we will test the mRNA+LNP construct in our human model systems and in mouse models of myocardial ischemia/reperfusion including transgenic strains that allow unequivocal assessment of cardiomyocyte division in vivo. We will then construct a GMP production line for the mRNA-LNP encapsulation technology to generate pilot batches for pig studies entailing catheter-based endomyocardial injection of the construct in a similar myocardial ischemia/reperfusion model. The final work package will be responsible for the management and coordination of the project, dissemination, intellectual property management and exploitation of REGeRNA results. This program is framed from the onset to lead to a phase 1 trial at completion.

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Abstract
(English)

Heart failure (HF) is a major health problem worldwide because of the high number of patients and the related costs. Current treatments are not consistently efficacious and fail to address the major underlying cause of HF: the massive loss of cardiomyocytes in damaged regions. REGeRNA has been designed to address this issue by leveraging advances in synthetic mRNAs and their lipid nanoparticle (LNP)-based carriers to generate a construct able to reactivate mechanisms mediating cardiomyocyte proliferation in development but which are shut-down shortly after birth. REGeRNA is organised in 6 work packages that follow a roadmap towards endogenous heart repair. The program starts tailoring various human assays and in vitro models such that they can reliably document cardiomyocyte proliferation. These will then be used for screening pathways thought to be involved in cardiomyocyte division, among which Hippo is our primary candidate. mRNA(s) encoding the relevant proteins will be subsequently synthesised and engineered such that their expression is restricted to cardiomyocytes and no stromal cell expansion occurs. An LNP formulation will then be developed for incorporation of the synthesized mRNA(s) and optimized for cardiomyocyte-specific delivery. Subsequently, we will test the mRNA+LNP construct in our human model systems and in mouse models of myocardial ischemia/reperfusion including transgenic strains that allow unequivocal assessment of cardiomyocyte division in vivo. We will then construct a GMP production line for the mRNA-LNP encapsulation technology to generate pilot batches for pig studies entailing catheter-based endomyocardial injection of the construct in a similar myocardial ischemia/reperfusion model. The final work package will be responsible for the management and coordination of the project, dissemination, intellectual property management and exploitation of REGeRNA results. This program is framed from the onset to lead to a phase 1 trial at completion.