Gene Therapy Knockdown of Hippo Signaling Induces Cardiomyocyte Renewal in Pigs After Myocardial Infarction

Authors

Shijie Liu
Ke Li
Leonardo Wagner Florencio
Li Tang
Todd R Heallen
John P Leach
Yidan Wang
Francisco Grisanti
James T Willerson
Emerson C Perin
Sui Zhang
James F Martin

Publication Date

6-30-2021

Journal

Science Translational Medicine

DOI

10.1126/scitranslmed.abd6892

PMID

34193613

PMCID

PMC9476348

PubMedCentral® Posted Date

9-15-2022

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Dependovirus, Disease Models, Animal, Genetic Therapy, Mice, Myocardial Infarction, Myocytes, Cardiac, Signal Transduction, Swine

Abstract

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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