Combinatorial miRNA1a/15b interference drives adult cardiac regeneration

BACKGROUND: Despite its promise, cardiac regenerative therapy remains clinically elusive due to the difficulty of spatio-temporal control of proliferative induction, and the need to coordinately reprogram multiple regulatory pathways to overcome the strict post-mitotic state of human adult cardiomyocytes. The present study was designed to identify a novel combinatorial miRNA therapy to address this unmet therapeutic need. METHODS: We performed a combinatorial miRNA interference screen specifically targeting cardiac-predominant miRNAs regulating key aspects of cardiomyocyte mitotic induction to cell-cycle completion, including sarcomerogenesis, metabolic and cell-cycle control pathways. Cardiomyocyte proliferation and cardiac function were assessed in human cardiac biopsies, human cardiac tissue mimetics and in mouse disease models. RESULTS: We identified combinatorial interference of miR-1a and miR-15b (LNA-1a/15b) as drivers of adult cardiomyocyte proliferation. Due to miR-1a/15b function on multiple processes modulating adult cardiomyocyte mitosis, its inhibition augmented adult cardiomyocyte cell-cycle completion and daughter cell formation, and improved contractility in in vitro 2D and 3D ischemic models, and in a mouse model of ST-segment elevation myocardial infarction (STEMI). Due to the cardiac-restricted pattern of miR-1a/15b expression, this strategy provides a feasible strategy for specific cardiomyocyte proliferative induction with minimal risk of neoplasm formation and off-target toxicity. CONCLUSIONS: Combinatorial miR-1a/15b inhibition drives mitotic re-entry in adult cardiomyocytes and improves cardiac function in response to myocardial infarction. Our data provides a novel and clinically feasible LNA-based anti-miR-1a/15b strategy to attenuate heart failure and highlights an underutilized therapeutic strategy for simultaneous co-regulation of multiple disease pathways through combinatorial miRNA interference.