LMNA-related cardiomyopathy: From molecular pathology to cardiac gene therapy

• A critical analysis of the existing LMNA-related cardiomyopathy disease models highlighting their discrepancy from human patients. • A comprehensive summary of the diverse disease mechanisms emphasizing the difficulty to develop small-molecule drugs to target all the mechanisms. • A review of the potential gene therapy strategies that could overcome the current obstacles in targeted therapy for LMNA-related cardiomyopathy. The genetic variants of LMNA cause an array of diseases that often affect the heart. LMNA -related cardiomyopathy exhibits high-penetrance and early-onset phenotypes that lead to late-stage heart failure or lethal arrhythmia. As a subtype of dilated cardiomyopathy and arrhythmogenic cardiomyopathy, LMNA -related cardiac dysfunction is resistant to existing cardiac therapeutic strategies, leaving a major unmet clinical need in cardiomyopathy management. Here we comprehensively summarize current knowledge about the genetic basis, disease models and pathological mechanisms of LMNA -related cardiomyopathy. Recent translational studies were highlighted to indicate new therapeutic modalities such as gene supplementation, gene silencing and genome editing therapy, which offer potential opportunities to overcome the difficulties in the development of specific drugs for this disease. LMNA -related cardiomyopathy involves many diverse disease mechanisms that preclude small-molecule drugs that target only a small fraction of the mechanisms. Agreeing to this notion, the first-in-human clinical trial for this disease recently reported futility. By contrast, gene therapy offers the new hope to directly intervene LMNA variants and demonstrates a tremendous potential for breakthrough therapy for this disease. Concepts in this review are also applicable to studies of other genetic diseases that lack effective therapeutics.