Chemically modified h CFTR mRNAs recuperate lung function in a mouse model of cystic fibrosis

Gene therapy has always been a promising therapeutic approach for Cystic Fibrosis (CF). However, numerous trials using DNA or viral vectors encoding the correct protein resulted in a general low efficacy. In the last years, chemically modified messenger RNA (cmRNA) has been proven to be a highly potent, pulmonary drug. Consequently, we first explored the expression, function and immunogenicity of human (h)CFTR encoded by cmRNA h CFTR in vitro and ex vivo , quantified the expression by flow cytometry, determined its function using a YFP based assay and checked the immune response in human whole blood. Similarly, we examined the function of cmRNA h CFTR in vivo after intratracheal (i.t.) or intravenous (i.v.) injection of the assembled cmRNA h CFTR together with Chitosan-coated PLGA (poly-D, L-lactide-co-glycolide 75:25 (Resomer RG 752 H)) nanoparticles (NPs) by FlexiVent. The amount of expression of human hCFTR encoded by cmRNA h CFTR was quantified by hCFTR ELISA, and cmRNA h CFTR values were assessed by RT-qPCR. Thereby, we observed a significant improvement of lung function, especially in regards to FEV 0.1 , suggesting NP-cmRNA h CFTR as promising therapeutic option for CF patients independent of their CFTR genotype.