Research ArticleGene Therapy

Gene therapy knockdown of Hippo signaling induces cardiomyocyte renewal in pigs after myocardial infarction

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Science Translational Medicine  30 Jun 2021:
Vol. 13, Issue 600, eabd6892
DOI: 10.1126/scitranslmed.abd6892

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Gene therapy for a failing heart

Heart failure, a leading cause of death worldwide, is partly due to poor renewal capacity of adult heart muscle cells (cardiomyocytes). Liu et al. used gene therapy to knock down the endogenous Hippo signaling pathway in cardiomyocytes of adult pigs after myocardial infarction. Hippo pathway knockdown induced these cells to undergo self-limiting division, resulting in effective tissue renewal with improved heart function in treated pigs. These findings suggest that Hippo pathway knockdown in cardiomyocytes may provide an opportunity for heart repair after injury in humans.


Human heart failure, a leading cause of death worldwide, is a prominent example of a chronic disease that may result from poor cell renewal. The Hippo signaling pathway is an inhibitory kinase cascade that represses adult heart muscle cell (cardiomyocyte) proliferation and renewal after myocardial infarction in genetically modified mice. Here, we investigated an adeno-associated virus 9 (AAV9)–based gene therapy to locally knock down the Hippo pathway gene Salvador (Sav) in border zone cardiomyocytes in a pig model of ischemia/reperfusion-induced myocardial infarction. Two weeks after myocardial infarction, when pigs had left ventricular systolic dysfunction, we administered AAV9-Sav–short hairpin RNA (shRNA) or a control AAV9 viral vector carrying green fluorescent protein (GFP) directly into border zone cardiomyocytes via catheter-mediated subendocardial injection. Three months after injection, pig hearts treated with a high dose of AAV9-Sav-shRNA exhibited a 14.3% improvement in ejection fraction (a measure of left ventricular systolic function), evidence of cardiomyocyte division, and reduced scar sizes compared to pigs receiving AAV9-GFP. AAV9-Sav-shRNA–treated pig hearts also displayed increased capillary density and reduced cardiomyocyte ploidy. AAV9-Sav-shRNA gene therapy was well tolerated and did not induce mortality. In addition, liver and lung pathology revealed no tumor formation. Local delivery of AAV9-Sav-shRNA gene therapy to border zone cardiomyocytes in pig hearts after myocardial infarction resulted in tissue renewal and improved function and may have utility in treating heart failure.

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