Validation of APT101 for the Treatment of Systemic Sclerosis-Associated Interstitial Lung Disease (SSc-ILD) in an Aging Murine Model

Abstract Systemic Sclerosis (SSc) is a rare autoimmune disease which carries the highest risk of mortality of all connective tissue diseases. Two major subgroups of SSc exist: limited cutaneous scleroderma characterized by dermal fibrosis, and diffuse cutaneous scleroderma characterized by fibrosis rapidly progressing to internal organs such as the lungs, kidneys, and heart. Diffuse cutaneous SSc is characterized by vascular dysfunction that initiates a cascade of inflammation and autoimmune responses leading to progressive organ fibrosis. Morbidity in SSc is largely driven by the development of SSc associated ILD (SSc-ILD) with fibrosis in the lungs. Pulmonary fibrosis is now the leading cause of death in patients with SSc-ILD. It is well established that vascular endothelial dysfunction is an important component and precursor of SSc-ILD. The apelin/apelin receptor (APJ) signaling axis on endothelial cells has been implicated as a crucial hub for both vascular development and repair. APJ-dependent signaling has also been shown to be critical for resolution of acute lung injury. Aging and injury have both been shown to confer reductions in endogenous apelin/APJ signaling, emphasizing reduced capacities for vascular repair and regeneration with persistent fibrosis in aging models of injury. While our foundational studies confirm the novel potential for selective APJ agonism as a therapeutic strategy, further investigation into (1) comparative efficacy in clinically relevant non- resolving aging murine model of pulmonary fibrosis and (2) the mechanistic effect of APJ agonism on underlying endothelial function in the fibrotic lung are necessary to de-risk clinical trial outcomes for this novel anti-fibrotic strategy in SSc-ILD. Studies with aging models of pulmonary fibrosis are critical for testing novel therapeutic strategies. Our preliminary results demonstrate that therapeutic treatment with APJ agonist, APT101, reduces lung fibrosis in young mice after bleomycin challenge. We hypothesize that selective therapeutic agonism with APT101 will promote vascular repair and regeneration following lung injury, resulting in less vascular permeability and reduced lung fibrosis. To better recapitulate human disease, we will use a non-resolving model of pulmonary fibrosis (bleomycin in young vs. aged mice) to demonstrate that therapeutic administration of APT101 limits fibrosis through reductions in vascular permeability and improved endothelial cell repair and regeneration in vivo (Aim 1). We will also validate the translational potential of APT101 using human lung endothelial cells in vitro to assess whether selective APJ signaling improves endothelial cell regenerative capacity (Aim 2). These STTR Phase I studies will help de-risk APT101 as it moves forward towards clinical translation.