Drug Discovery for Adult Cardiomyocyte Regeneration: Opportunities and Challenges

Cardiovascular disease is a major contributor to human mortality and morbidity. The cardiac tissue undergoes fibrotic healing after injury because of the limited regenerative capacity of adult mammalian cardiomyocyte (CM). Extensive research has been performed to identify therapeutic targets for CM regeneration, as the success of promoting adult human CM regeneration to repair the injured heart is considered the Holy Grail in the field. To date, more than 30 target genes have been shown to regulate adult mammalian CM proliferation. More than 20 targets have been validated in adult mouse myocardial infarction (MI) model in a therapeutic setting. In this review, the translational efficacy readouts from 17 selected pharmaceutical targets are summarized, among which the Hippo-yes-associated protein (Yap) pathway is the most extensively investigated and fits the criteria for a promising target for pro-CM-regeneration therapy development. As the pro-CM-regeneration potential of current drug treatment for cardiovascular patients is limited, to help identify and fill the gap between basic research and drug discovery in this specific field, details regarding target identification, validation in mouse MI models, high-throughput screening assay development, and preclinical in vivo efficacy model optimization are discussed. Finally, suggestions and recommendations are also provided to help establish a common guideline for in vivo translational studies for drug discovery focusing on CM regeneration. Antioxid. Redox Signal. 39, 1070-1087.