Therapeutic base editing alleviates restrictive cardiomyopathy.

Abstract

Restrictive cardiomyopathy (RCM) is a severe cardiac disorder characterized by impaired ventricular filling and diastolic dysfunction, with mutations in sarcomeric proteins representing major causative factors. Mutations of TNNI3 gene (e.g., p.R192H) constitute major genetic causes of RCM, particularly affecting pediatric patients and being associated with poor prognosis. Here, we demonstrate that adenine base editor (ABE) can effectively correct RCM-causing mutation and alleviate RCM in a murine model. We develop a murine model harboring the Tnni3^R193H mutation that recapitulates the hallmark features of human RCM. Importantly, targeted delivery of ABE via adeno-associated virus (AAV) can achieve efficient and precise correction of the Tnni3^R193H mutation in adult RCM mice, leading to significant improvement of cardiac functions. Our findings establish base editing as a therapeutic strategy for RCM and highlight its broader potential for treating genetic cardiomyopathies in clinical settings.