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ZeNewCardio: Discovering Heart Regeneration Therapies Through Zebrafish

Periodic Reporting for period 1 - ZeNewCardio (ZeNewCardio: Discovering Heart Regeneration Therapies Through Zebrafish)

Reporting period: 2019-06-01 to 2021-05-31

Myocardial infarction (MI) is one of the leading causes of death worldwide. In 2020, MI is estimated to have affected around 126 million people (approximately 1.8 % of world’s population). Individuals suffering from heart attacks die immediately or within days of the event. Unfortunately, a very high percentage of survivors also die in later years (~ 30%). This is mainly due to the development of heart failure since damaged human cardiac tissue is not able to recover its structure and function after damage. Regenerative medicine aims at improving the function of the infarcted heart in order to avoid or reduce the possibility of developing heart failure. Interestingly, unlike mammals which show insufficient regenerative capacity, the zebrafish, an emerging research organism in translational research, has the lifelong ability to fully recover their myocardial function upon injury. The ZeNewCardio project has been focused on the development of strategies to discover potential mechanisms activating cardiac regeneration conserved between fish and humans. We aimed to use the gathered knowledge to open new therapeutic venues for human infarction. The results have revealed novel regulators of myocardial recovery and have led to the development of compounds with potential pro-regenerative effects on injured mammalian hearts.
The MSCA-funded project aimed at exploiting the regenerative potential inherent in zebrafish to discover new cardio-regenerative targets, with the hypothesis that pharmacological modulation of those targets would allow heart recovery in patients who have suffered a myocardial infarction.

Throughout the project, we have achieved the main following results:
- Development of a medium-throughput preclinical platform using the zebrafish model to find suitable treatments for heart regeneration after ischemia.
- Implementation of cardiac injury models in zebrafish.
- Identification and in vivo/in vitro validation of a master regulator of cardiac regeneration.
- Screening of patentable molecules modulating the function of the genetic targets identified.

The key achievement of the research program is the discovery and validation of a promising novel “anti-regenerative” therapeutic target followed by identification of different small molecules that inhibit its activity. These molecules, by inhibiting a target that represses regeneration, have the potential to promote cardiac regeneration in infarcted hearts. Importantly, the project developed further than expected towards more advanced preclinical phase since the inhibitory molecules identified against the target (Hits) are in the “Hit-to-Lead” process, which precedes the beginning of the regulated preclinical phase (validation in other animal models as rodents and pigs). Importantly, the results obtained can be protected by a patent. To this aim, the process of intellectual protection (IP) has been started. Once the IP is performed, we expect to publish high impact articles describing a novel mechanism of heart regeneration.
To date there are no viable clinical therapies to treat myocardial infarction other than heart transplantation, which cannot be implemented on a large scale. The most advanced and promising strategies developed during the last years to meet patient’s demand are cardiac stem cell therapy. Nevertheless, this approach has multiple medical and economic disadvantages:
i) experimental difficulty in obtaining the high number of cells required for cell treatment;
ii) surgical difficulty in administering these cells to damaged heart tissue, which also leads to immunosuppression of the patient, which means all this as a risk for their survival;
iii) biological barriers inherent to the heart - immune system, low proliferative environment - that prevent the administered cells from penetrating the damaged tissue, colonizing it and improving the function of the infarcted heart; and
iv) high cost, to obtain enough mature cardiomyocytes and to perform the surgery that allows their administration in the infarcted tissue.
All these disadvantages mean that, even if these types of therapies are approved by regulatory bodies, they can only be used in some cases, and in those health systems that have the means and experience to carry out this type of intervention. Therefore, a pharmacological strategy appears a more feasible solution than surgical intervention and can be accessible to all patients.

The candidate molecules identified in this project could provide a high-value therapeutic alternative - easy administration, low toxicity / side effects, and high therapeutic activity - for heart attack patients. Furthermore, there is no cardio-regenerative drug on the market, so our clinical candidate would only have to demonstrate efficacy, without the need to compare its therapeutic superiority against other commercialized therapeutic standards. Thus, if expected results are promising in the following phases of the project, our clinical candidate will have high possibilities of both medical and commercial success. We expect the results of this project to have a profound impact on the treatment of cardiovascular diseases as it will lead to new cardiac regenerative strategies able to replace the lost myocardial tissue, thereby reverting the conditions that lead to heart failure. These new strategies will address the urgent need to reduce the ischemia-related heart failure tolls on premature deaths, morbidity and economic burden in our society. Finally, our work will not only bring to the market novel molecules for enhancing heart regeneration in humans but also move the field of regenerative medicine towards refined and more effective solutions.
Zebrafish heart