Drug compound can reverse cardiomyopathy

A drug compound that could reverse hereditary disease arrhythmogenic cardiomyopathy (ACM) has been found by researchers in America. Zebrafish provided a screenable model of the disease with a cardiac myocyte-specific expression of a human mutation in the gene encoding plakoglobin, known to cause the disease in humans. The model allowed researchers to identify the mechanisms underlying this disease – which damages the muscles of the heart’s ventricles – and to find potential drugs to prevent its onset. Researchers were able to see clear evidence of heart disease after 48 hours of embryonic development. High-throughput screening enabled them to test 4,800 chemicals to identify a suppressor of the disease phenotype. SB216763 showed a remarkable ability to prevent or reverse the disease in fish, and researchers hoped this would hold true for humans. Their hopes were confirmed by studies of both mammalian models of ACM and human heart muscles derived from adult stem cells from patients with ACM. “We found that a single small molecule (SB216763) could reverse both the muscle cell injury and the arrhythmia components of ACM,” said Jeffrey E Saffitz, Professor of Pathology at Harvard Medical School. “These new findings provide strong evidence that the complex disease processes are linked to a common mechanism, which appears to involve a defect in forward trafficking of key proteins to the intercalculated disc, sites of cell-cell adhesion.” Saffitz said his team also appears to have discovered a new mechanism-based anti-arrhythmic drug that prevents or reverses major abnormalities of cellular electrophysiology in the heart in cases of ACM. “This work shows that it is possible to model a complex human disease in fish and use high-throughput screens of large chemical libraries for the discovery of effective new drugs and could help provide the foundation for future chemical biology efforts to bring such drugs to clinical use.” The work, published in Science Translational Medicine, involved researchers at Beth Israel Deaconess Medical Center and Brigham and Women’s Hospital. Identification of a New Modulator of the Intercalated Disc in a Zebrafish Model of Arrhythmogenic Cardiomyopathy