Inhaled mRNA therapy for treatment of primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder caused by mutations in one of at least 50 different genes that encode proteins involved in the biogenesis, structure, or function of motile cilia. Genetically inherited defects in motile cilia cause PCD, a debilitating respiratory disease for which there is no approved therapy. The dynein axonemal intermediate chain 1 (DNAI1) protein is a key structural element of the ciliary outer dynein arm (ODA) critical for normal ciliary activity and subsequent clearance of mucus from the conducting airways in humans. Loss-of-function mutations in DNAI1 account for up to 10% of all PCD cases, with functional abnormalities in patients presenting at or near birth and leading to a life-long course of disability, including progressive loss of lung function and bronchiectasis by adulthood. This underscores the significant unmet need for disease-modifying treatments that restore ciliary activity and mucociliary clearance in PCD patients. In this work, we demonstrate that lipid nanoparticle (LNP)-formulated human mRNA can be delivered as an aerosol to primary human bronchial epithelial cell models and to nonhuman primate (NHP) lungs. Additionally, we show that delivery of aerosolized LNP- mRNA to NHPs leads to detectable levels of newly translated human DNAI1 protein, at doses that overlap with exposures in an in vitro cell-based PCD model enabling rescue of ciliary function. Therefore, these data support further development of the inhaled mRNA therapy in clinical studies as a potential disease-modifying treatment for PCD.