Reducing Granules Without Splicing Restoration Alleviates RBM20 Cardiomyopathy | Circulation Research
BACKGROUND: RBM20 (RNA binding motif protein 20) cardiomyopathy is a severe form of dilated cardiomyopathy (DCM). Genetic variants in the nuclear localization signal of Rbm20 hinder its nuclear import and promote cytoplasmic pathogenic RNP (ribonucleoprotein) granules. We aimed to investigate whether reducing RNP granules by inhibiting Rbm20 expression could alleviate the DCM phenotype in Rbm20 S639G (Rbm20S639G) knock-in mice. METHODS: We downregulated Rbm20, utilizing antisense oligonucleotides (ASOs) that specifically inhibit Rbm20 expression. We administered Rbm20-ASOs in Rbm20S639G mice that carry a serine-to-glycine substitution in the nuclear localization signal of RBM20. The Rbm20-ASOs were administered subcutaneously at 25 mg/kg once a week for 8 weeks in both young (14-day-old) mice before the onset of DCM and adult (3-month-old) mice with established DCM phenotype. In vivo cardiac function was assessed by echocardiography. RNP granules were identified through fluorescent imm
