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New-generation cardiac therapeutic strategies directed to the activation of endogenous regenerative mechanisms

Periodic Reporting for period 2 - REANIMA (New-generation cardiac therapeutic strategies directed to the activation of endogenous regenerative mechanisms)

Reporting period: 2021-01-01 to 2022-06-30

Cardiovascular diseases remain the leading cause of death in the developed world. Each year cardiovascular disease (CVD) causes 3.9 million deaths in the Europe and over 1.8 million deaths in the 28 countries of the European Union (EU). I In 2015, more than 85 million people in Europe were living with CVD. In particular, ischemic heart disease remains the single most frequent death cause in Europe for both females (20%) and males (19%), of which more than a third represent premature deaths (<75 years old). In a majority of patients, ischemic heart disease first manifests in the form of acute myocardial infarction (AMI), which is the most common cause of HF worldwide. Risk of HF strongly correlates with the amount of lost myocardial tissue due to acute ischemia/reperfusion. The low regenerative response of the human heart underlies the inability in restoring the lost cardiomyocyte population and the persistence of scarred tissue, which frequently leads to arrhythmia, impaired pumping efficiency and HF. Currently, the only definitive cure for end-stage HF is heart transplant, however, even in the leader countries in organ transplant rates, the available donations fall largely below patient needs.

In response to this need, in the last two decades potential therapies aiming to regenerate the lost myocardium following AMI have been object of intense basic and clinical research. Unfortunately, clinical strategies in the field of regenerative cardiology, mostly based on implantation of cells, have so far yielded unsatisfactory outcomes.

The global objective of REANIMA is to change the current paradigms underlying clinical efforts towards cardiac regeneration, by transforming basic knowledge on new endogenous regenerative pathways into effective new therapies for patients at risk of heart failure subsequent to acute myocardial infarction.

The operational objectives of REANIMA are:

A) Achieve a comprehensive chart of mechanisms and pathways that promote adult mammalian heart regeneration, identifying the best hubs in the network for activating the endogenous regenerative ability of the heart.

B) Develop an optimized translational pipeline ensuring that the new regenerative mechanisms identified translate into clinical trials.
REANIMA scientists have identified a new factor specifically expressed in a subset of pro-regenerative cardiomyocytes in fishes that spontaneously regenerate their hearts. On the other side, they have generated genetic tools and molecular approaches that allow the classification and functional testing of different populations of cardiac fibroblasts in regenerative animals (axolotl and zebrafish). The specific involvement of these cell populations in heart regeneration are currently being analyzed by the members of the consortium. REANIMA scientists have also established new approaches for single-cell mRNA sequencing from adult cardiomyocytes, a procedure that currently bears important limitations in the scientific community.

Moving along the translational pathway, REANIMA scientists have screened hundreds of factors affecting sarcomere protein degradation. As a result, they isolated two factors essential in the regulation of sarcomere stability and cardiomyocyte proliferation. The factors identified have been studied in a mouse model of myocardial infarction (MI), showing positive results. After thorough study in the rodent model, these factors will be ready to progress along the translational pipeline towards large animal models testing. Working in the mouse model, REANIMA scientists have been able to test the role of Erbb2 in restoring heart function during the chronic phase on MI. The results obtained were very positive, indicating that even in a remodelling heart with a consolidated scar, this treatment is effective.

Moving into areas of research closer to the clinical application, Agrin efficacy in improving heart function after AMI in the pig has been tested in two independent studies in different laboratories. One of the studies yielded positive results in terms of safety and efficacy of the treatment and has been published. The second study has been completed and its results are currently been analyzed. The effects of Agrin have been assessed as well in a model of chronic MI in rats, yielding an improved function following the treatment. On the other side, mir-199a has been tested in a model of chronic MI in pigs. In this case, the results were negative in terms of improving heart function and, in addition, produced fatal arrhythmias due to long-term expression of the miRNA. Given that previous results indicated a clear pro-regenerative effect of miRNA-199a during AMI, new ways are being explored for the transient delivery of this pro-regenerative factor in the pig model. To this end, REANIMA scientists have developed a novel nanoparticle formulation that efficiently delivers the concentrated miRNA, and demonstrated efficacy in vitro and in the mouse heart.

Finally, REANIMA scientists have generated a new model of cardiac injury in human engineered heart tissues. Using cryoinjury as an approach, they showed the loss of myocardial tissue and the inability of the damaged muscle to regain contractile force following cryoinjury. This model provides for the first time a functional platform for testing regenerative treatments in human myocardial tissue.
MAJOR EXPECTED IMPACTS:

(i) REANIMA will produce innovative experimental therapies for heart regeneration, thereby targeting the heart failure, a disease without cure with devastating impacts on society and individuals.

(ii) REANIMA will transform the European capacities in Translational Regenerative Cardiology. REANIMA translational pipeline will build on the synergy of individual partner’s expertise to produce a true iterative process for harnessing newly gained knowledge and transforming it into effective therapies to be tested in clinical trials. We expect that the systematic exploration of the translational space in regenerative cardiology and the improved credibility of REANIMA pre-clinical research will boost the opportunities for further agreements with industrial partners or public funding bodies in the development of clinical trials.

(iii) INNOVATION POTENTIAL. Identification of new targets in cardiac regenerative medicine and development of new therapeutic strategies to target them. New translational platforms, like the zebrafish cardiac regeneration platform and the iPS-derived hEHT platform, will predictably will be of great interest both for academic and industrial stakeholders. In particular the combination of iPS-derived tissue engineering and pro- proliferative treatments is new and a potential target for IP protection and future development of personalized medicine platforms.

IV) Economic impact. In addition to the impact on morbidity, mortality, and lifetime productiveness, HF places a huge burden on health-care resources. A therapy that could either prevent progression to heart failure after AMI or improve the function of failing hearts could have a major impact on the standard of care and the economy. As opposed to chronic handling of an incurable disease, the paradigm of regenerative medicine aims to cure disease by producing new tissue that restores cardiac function long-term.
Representation of nanoparticles containing therapeutic miRNAs fro therapeutic delivery
REANIMA translational pipeline
Mosaic overexpression in the mouse myocardium
Human engineered heart tissues as in vitro models and source for regenerative implantation