D29-01 Targeting Senescence-associated Transcription Factors as a Strategy to Eliminate Senescent Cells for Pulmonary Fibrosis Therapy

Abstract Rationale Cellular senescence is a central driver of pulmonary fibrosis pathogenesis. Senescent cells foster a persistent pro-fibrotic microenvironment via their Senescence-Associated Secretory Phenotype (SASP), thereby directly promoting fibroblast activation and aberrant extracellular matrix deposition. This self-amplifying cycle is a key engine of disease progression, making the targeted elimination of senescent cells a promising therapeutic avenue. A critical challenge, however, lies in the marked heterogeneity of senescent cells, whose definitive identification requires multiple biomarkers. Therefore, developing highly specific methods to target and clear these cells is of paramount importance for translating this strategy into reality. Methods Employing synthetic biology, we screened and re-engineered core regulatory elements from senescence-associated promoters to create a highly specific and sensitive genetic sensor for cellular senescence. The sensor’s robust performance was validated in multiple in vitro senescence models (bleomycin-induced, H-RAS oncogene-induced, and stress-induced). We then packaged it into a replication-deficient adenoviral vector, which demonstrated potent and specific elimination of senescent cells in both cellular and in vivo pulmonary fibrosis models. Results Following sequence optimization, the senescence biosensor exhibited robust and specific activation in diverse cellular senescence models. Correspondingly, the engineered adenoviral vector enabled the highly efficient and specific elimination of senescent cells in culture. Crucially, this therapeutic strategy significantly enhanced survival in a mouse model of pulmonary fibrosis upon intravenous delivery. Ultimately, histological evidence solidified this outcome, revealing a pronounced attenuation of pulmonary fibrosis and a concomitant decrease in senescent cell load. Conclusion By specifically targeting senescent cells for clearance, we can effectively mitigate the progression of pulmonary fibrosis, which paves the way for a novel therapeutic strategy against idiopathic pulmonary fibrosis (IPF). This abstract is funded by: None