Abstract 14651: Noncoding RNA Drug, TY1, Attenuates Cardiac Fibrosis in Two Mouse Models of Systemic Sclerosis

• Published in: Circulation (New York, N.Y.) Vol. 148; no. Suppl_1
• Main Authors: Jones, Xaviar M, Ciullo, Alessandra, Mesquita, Thassio, Fournier, Mario, Liu, Weixin, Li, Liang, Ibrahim, Ahmed G, Marban, Eduardo
• Format: Journal Article
• Language: English
• Published: 07.11.2023
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.148.suppl_1.14651

Abstract only Introduction: Systemic sclerosis (SSc) is a connective tissue disease characterized by inflammation and fibrosis of the skin and vital organs. The disease has no specific treatment options and a high mortality (~30% at 3 years). We have previously demonstrated anti-fibrotic and anti-inflammatory properties of EV-YF1, a small Y RNA abundant in extracellular vesicles secreted by cardiosphere-derived cells (CDCs). Here we describe the therapeutic bioactivity of a shorter, engineered derivative, TY1. Methods: 5-7-week-old female C57BL/6J wild type mice (n=100 total) were injected with phosphate-buffered saline (PBS; WT) or 100 μL bleomycin (1 mg/ml) subcutaneously every other day for 3 weeks. Animals then received either vehicle (formulation only, in PBS), TY1, or scrambled TY1 (as an RNA control) via oral gavage. Endpoints include exercise capacity, lung weight, systolic and diastolic function by echocardiography, and histologic quantification of fibrosis in heart and skin. To confirm the antifibrotic findings in an inflammation-independent model, 4-6-week-old Tight-skin (tsk-1) mice (n=18 total) received oral TY1, scramble or vehicle for 4 weeks. Results: Diastolic dysfunction was evident in bleomycin mice, but was normalized by TY1 ingestion (E/E’ ratios in WT: 18.91, vehicle: 32.29, scramble: 36.19, TY1: 20.65 p <0.0001). Likewise, lung congestion and exercise intolerance were ameliorated by TY1 ingestion (p<0.0001). In both models (bleomycin-induced and tsk-1), skin and cardiac fibrosis were greater in vehicle or scramble groups than in WT, but were normalized by TY1 after 4 weeks (p <0.001). Conclusions: These results demonstrate the therapeutic bioactivity of a bioinspired new chemical entity in two complementary mouse models of SSc. Thus, TY1 merits investigation as a potential novel therapeutic for SSc.