RNA Toxicity and Cardiac Pathology

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Project Summary: Myotonic dystrophy (DM1), the most common form of muscular dystrophy in adults and children, is an autosomal dominant genetic disorder caused by an expanded CTG repeat in the DM protein kinase (DMPK) gene that leads to nuclear retention of the mutant RNA and subsequent RNA toxicity. The heart is one of the primary organs affected in DM1. Cardiac conduction problems are present in up to 75% of adult DM1 cases, and sudden death due to cardiac arrhythmias is one of the most common causes of death in DM1. Unfortunately, the pathogenesis of cardiac manifestations in DM1 is not well understood. Clinical focus for cardiac disease in DM1 has been on arrhythmias and conduction abnormalities. Of note, the pathology of cardiac defects in DM1 has been historically associated with interstitial fibrosis, and fatty infiltration and fibrosis of cardiac conduction tissues. We reported the first inducible mouse model of RNA toxicity and cardiac conduction defects and demonstrated the potential for reversibility of DM1 phenotypes by silencing toxic RNA production. Recently using the DM200 mouse model, we showed for the first time, the potential for antisense oligonucleotides (ASOs) to treat cardiac disease in DM1. We also found evidence for fibrotic changes associated with RNA toxicity in the heart. In the past decade, the advent of new cardiac MRI studies has led to evidence of and an increased interest in understanding cardiac fibrosis in DM1 and its role in the clinical pathology of DM1. We propose to use the DM200 mouse model as a tool for developing and investigating these ideas and concepts in a pre-clinical model and to try to understand the cellular and molecular drivers of fibro-adipogenic changes in the heart. We will do this through three independent but complementary aims. First, we will develop and evaluate cardiac MRI as a biomarker for RNA toxicity in the heart. Second, we will determine the role of cardiac PDGFRA+ve cells in fibro/adipogenic pathologic responses to RNA toxicity in the heart. Third, based on preliminary evidence of increased TGFβ in the heart, we will characterize the role of TGFβs in RNA toxicity in the heart, and study the therapeutic response to therapies targeting fibrosis and TGFβ (including isoform specific antibodies against TGFβ2 and TGFβ3). Importantly, we will validate the CMR protocols and parameters in therapeutic trials using: a) next generation ASOs that target the toxic RNA and b) the therapies targeting fibrosis and TGFβs. Our goals are to understand the drivers of cardiac pathology associated with RNA toxicity in DM1, and to evaluate and establish the potential utility of cardiac MRI as a tool to monitor disease progression and response to therapy.