LUNETA

Patients with chronic obstructive pulmonary disease (COPD) suffer from chronic lung inflammation, tissue remodeling and persistent airflow limitation. Although corticosteroids and bonchodilatators can reduce the mortality risk, they still marginally improve lung function. There is an urgent need to 1) identify new therapeutic drugs, reducing inflammation and tissue remodeling, 2) design drug delivery strategies tailored to the COPD epithelium environment. In this project, we want to develop RNA therapy for COPD using lipid nanoparticles (LNP) targeted to the lung epithelium and assess these innovative therapies in relevant models. In a first step, we will optimize lipid nanoparticles for mucus penetration, since COPD induces mucus oversecretion, using alternative polymers to poly(ethylene glycol), which toxicity has raised concerns recently. In a second step, we will add a specific ligand – an aptamer - to improve specific cell uptake by the lung epithelium. In parallel, we will examine siRNAs that target molecules involved in mucus oversecretion and tissue remodeling of COPD. Both RNA candidates and delivery systems will be assessed on a 2D culture of human bronchial epithelial cells (BECs) at the air-liquid interface (ALI). Finally, the optimal system will be evaluated in a 3D innovative tubular organoid system, modelling distal bronchi, with the ability to infuse drugs into the lumen and measure clinically pertinent endpoints. This project brings together a polymer chemist, expert in polymers with similar stealth properties to PEG, a drug delivery scientist, expert in lipid nanoparticles and aptamers, and a lung physiologist, expert in preclinical models of COPD. While carefully evaluating toxicity, off-target and immunostimulatory effects, we aimed at bringing solid pre-clinical evidences of RNA drugs, obtained in 2D and 3D models made of patient’s cells, and provide a framework to translate preclinical findings to clinical settings.