A next-generation CTGF inhibitor to suppress pulmonary fibrosis in pneumoconiosis

Pneumoconiosis is a pulmonary disease caused by occupational exposure to silica dust, leading to severe pulmonary fibrosis. The connective tissue growth factor (CTGF), a central mediator of pulmonary fibrosis, contains two functional domains (VWC and CT) contributing to the fibrosis activity of CTGF, indicating their potential as therapeutic targets. However, a VWC-domain specific antibody (FG3019) failed in the phase III clinical trial for idiopathic pulmonary fibrosis (IPF). Our data indicated that the CT-domain contributed more to fibrosis activity of CTGF than VWC-domain. Therefore, it is desirable to develop a next generation of CTGF inhibitor to target CTGF CT-domain. Using an AI-driven aptamer screening procedure, an aptamer (Apc003) and its long-lasting modification form (Apc003OA) were developed, outperforming FG-3019 in fibroblast and a Duchenne Muscular Dystrophy mouse model, respectively, which received an Orphan Drug Designation from the US FDA. In our pulmonary fibrosis mouse model, preliminary data implied that Apc003OA might exert better anti-fibrosis activity than FG-3019. The proposed work aims to determine whether Apc003OA could exert anti-fibrosis activity in a dose-dependent manner, and exert better antifibrosis activity than FG-3019 in a bleomycin-induced pulmonary fibrosis mouse model, which would facilitate the next generation of CTGF inhibitor to suppress pulmonary fibrosis in pneumoconiosis and promote the translation in Orphan Drug Designation.