MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs

Khatia Gabisonia, Giulia Prosdocimo, Giovanni Donato Aquaro, Lucia Carlucci, Lorena Zentilin, Ilaria Secco, Hashim Ali, Luca Braga, Nikoloz Gorgodze, Fabio Bernini, Silvia Burchielli, Chiara Collesi, Lorenzo Zandonà, Gianfranco Sinagra, Marcello Piacenti, Serena Zacchigna, Rossana Bussani, Fabio A. Recchia () and Mauro Giacca ()
Additional contact information
Khatia Gabisonia: Institute of Life Sciences, Scuola Superiore Sant’Anna
Giulia Prosdocimo: International Centre for Genetic Engineering and Biotechnology (ICGEB)
Giovanni Donato Aquaro: Fondazione Toscana Gabriele Monasterio
Lucia Carlucci: Institute of Life Sciences, Scuola Superiore Sant’Anna
Lorena Zentilin: International Centre for Genetic Engineering and Biotechnology (ICGEB)
Ilaria Secco: International Centre for Genetic Engineering and Biotechnology (ICGEB)
Hashim Ali: International Centre for Genetic Engineering and Biotechnology (ICGEB)
Luca Braga: International Centre for Genetic Engineering and Biotechnology (ICGEB)
Nikoloz Gorgodze: Institute of Life Sciences, Scuola Superiore Sant’Anna
Fabio Bernini: Institute of Life Sciences, Scuola Superiore Sant’Anna
Silvia Burchielli: Fondazione Toscana Gabriele Monasterio
Chiara Collesi: International Centre for Genetic Engineering and Biotechnology (ICGEB)
Lorenzo Zandonà: Surgical and Health Sciences, University of Trieste
Gianfranco Sinagra: Surgical and Health Sciences, University of Trieste
Marcello Piacenti: Fondazione Toscana Gabriele Monasterio
Serena Zacchigna: Surgical and Health Sciences, University of Trieste
Rossana Bussani: Surgical and Health Sciences, University of Trieste
Fabio A. Recchia: Institute of Life Sciences, Scuola Superiore Sant’Anna
Mauro Giacca: International Centre for Genetic Engineering and Biotechnology (ICGEB)

Nature, 2019, vol. 569, issue 7756, 418-422

Abstract: Abstract Prompt coronary catheterization and revascularization have markedly improved the outcomes of myocardial infarction, but have also resulted in a growing number of surviving patients with permanent structural damage of the heart, which frequently leads to heart failure. There is an unmet clinical need for treatments for this condition1, particularly given the inability of cardiomyocytes to replicate and thereby regenerate the lost contractile tissue2. Here we show that expression of human microRNA-199a in infarcted pig hearts can stimulate cardiac repair. One month after myocardial infarction and delivery of this microRNA through an adeno-associated viral vector, treated animals showed marked improvements in both global and regional contractility, increased muscle mass and reduced scar size. These functional and morphological findings correlated with cardiomyocyte de-differentiation and proliferation. However, subsequent persistent and uncontrolled expression of the microRNA resulted in sudden arrhythmic death of most of the treated pigs. Such events were concurrent with myocardial infiltration of proliferating cells displaying a poorly differentiated myoblastic phenotype. These results show that achieving cardiac repair through the stimulation of endogenous cardiomyocyte proliferation is attainable in large mammals, however dosage of this therapy needs to be tightly controlled.

Date: 2019
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DOI: 10.1038/s41586-019-1191-6

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