Abstract 13813: Novel Noncoding Y RNA Drug Attenuates Fibrosis and Diastolic Dysfunction in Systemic Sclerosis

Introduction: Scleroderma is an autoimmune disease characterized by early vasculopathy, and fibrosis of the skin, heart and lung, resulting in irreversible scarring and organ failure. Current therapy only mitigates symptoms with no available curative options. 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. Here we describe the therapeutic bioactivity of a shorter, engineered derivative, TY4. Methods: TY4, a 24-nucleotide chemically-modified oligonucleotide bioinspired by EV-YF1, was synthesized and packaged into lipid nanoparticles. To create a model of systemic sclerosis, C57BL/6J wild type mice (n=100 total) were injected with 100 μL bleomycin or PBS (control) subcutaneously every other day for 3 weeks. Animals then received either vehicle (0.9% NaCl), TY4 scrambled (as an RNA control) or TY4 via oral gavage. Endpoints include body weight, exercise capacity, echocardiography, and histologic quantification of fibrosis in heart and skin. Results: At study endpoint, animals receiving TY4 demonstrated body weight recovery (p<0.0001) and augmented exercise capacity (p<0.0002) compared to vehicle and TY4 scrambled. Similarly, cardiac fibrosis (p<0.0001) and dermal thickness (TY4 287 ± 45 μm, TY4 scrambled 426 ±75 μm , vehicle 419 ±116 μm p<0.0001) were largely normalized after TY4 administration. Diastolic dysfunction, as measured by echocardiography (E/E’), was present in controls but reverted to normal after TY4 administration (p<0.0001). Conclusions: These results demonstrate the therapeutic bioactivity of a bioinspired new chemical entity with the potential to become a synthetic, off-the-shelf drug for systemic sclerosis.