Abstract Rationale Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory condition without a curative treatment, caused by tobacco smoking as well as environmental contaminants, including particulate matter, and heavy metals, including lead (Pb) and cadmium (Cd). Because efficient therapeutic strategies for COPD are limited, it is necessary to discover novel therapeutic targets for COPD and develop new strategies to modulate these targets. Ninjurin1 (Ninj1) is a cell adhesion molecule that exerts various biological functions for regulating inflammation and lytic cell death. This study is aimed at developing Ninj1-targeting antisense oligonucleotides (ASOs) to alleviate COPD induced by chronic inhalation of Pb and Cd. Method We designed and synthesized various Ninj1-targeting antisense oligonucleotides, then evaluated their efficacy in downregulating Ninj1 expression in vivo. By employing the established Pb/Cd-induced COPD model, we evaluate the efficacy of Ninj1 ASOs to suppress Pb/Cd-mediated COPD development. We also evaluated the systemic toxicity of Ninj1 ASOs after intratracheal administration. Results Lead Ninj1-targeting ASO candidates effectively suppressed Ninj1 expression in the lungs of mice at both mRNA and protein levels. Intratracheal delivery of these ASOs significantly mitigated Pb/Cd-induced COPD phenotypes in mice, including mucus hypersecretion, alveolar airspace enlargement, aberrant matrix metalloproteinase activity, oxidative stress, apoptosis, and excessive accumulation of macrophages and neutrophils. Flow cytometry revealed effective silencing across pulmonary cell populations, with the most pronounced and preferential knockdown observed in macrophages. Moreover, high-dose and extended local administration resulted in no apparent systemic toxicity, with normal organ histology, blood chemistry, and body weight preserved. Conclusion These results illustrate the therapeutic promise of Ninj1-targeting ASOs as an low-toxicity approach to mitigate COPD development. This abstract is funded by: Ministry of Science of ICT (MSIT), Republic of Korea (grant no. RS-2024-00441449)
Lee et al. (Fri,) studied this question.