Unraveling the pathogenesis of familial dilated cardiomyopathy towards precision medicine

Summary Dilated cardiomyopathy (DCM) is a leading cause of heart failure and death. Despite the progress in unraveling the genetic basis of DCM, there is a lack of disease-modifying therapies that target the underlying genetic etiology. In preliminary studies, we identified the transcription factor 4 (ATF4) as a potential target for therapeutic interventions in genetic DCM. ATF4 is a critical factor mediating the integrated stress response; an adaptive pathway activated in response to stress. ATF4 is selectively translated in response to specific forms of cellular stress to induce the expression of genes involved in adaptation to stress. Here we propose a multidisciplinary approach to explore the potential role of ATF4-mediated regulation of one-carbon metabolism in cardiac physiology and develop novel mutation-agnostic gene therapy for DCM. In Aim 1, we will test whether ATF4 overexpression can rescue the contractility deficit, a hallmark of DCM, in a mutation-agnostic manner using iPSC-CMs derived for patients carrying DCM-causing mutation in diverse gene ontologies. In Aim 2, we will examine the potential role of ATF4-mediated regulation of one-carbon metabolism gene expression in cardiomyocyte function. In Aim 3, we will use AAV-mediated overexpression of ATF4 in vivo and test whether ATF4 signaling could reverse or halt the progression of DCM in vivo. Unlike conventional gene therapies, our approach does not replace a faulty or missing gene. Instead, our approach aims at triggering a cardioprotective effect by bolstering the ATF4-dependent one-carbon metabolism gene expression in the heart. We hope to provide proof-of-concept for a new clinically relevant therapeutic strategy, paving the way for mutation-agnostic treatments for genetic DCM. Such treatments are likely to apply to other types of cardiac diseases such as heart failure.