mRNA transcript therapy of primary respiratory epithelial cells derived from PCD individuals with bi-allelic CCDC40 mutations

Introduction Primary Ciliary Dyskinesia (PCD) is characterized by impaired mucociliary clearance and progressive airway damage due to dysfunctional motile cilia in the airways and more than 50 genes are associated with PCD. Clinical care is symptomatic and no causal treatment is available. We studied the feasibility of mRNA therapy to correct the molecular defect in human respiratory epithelial cells (hRECs) from PCD individuals with bi-allelic disease-causing variants in Coiled-Coil Domain Containing 40 (CCDC40). In CCDC40 deficient cells, ciliary beating is hampered due to microtubular disorganization, and loss of CCDC40 binding partners Coiled-Coil Domain Containing 39 (CCDC39), Growth Arrest Specific 8 (GAS8) and Dynein Axonemal Light Intermediate Chain 1 (DNALI1). Here, we provide proof-of-concept (PoC) that Stabilized Non-Immunogenic mRNA (SNIM RNA) rescues ciliary defects.