Modified hCFTRmRNA restores normal lung function in a mouse model of cystic fibrosis

AbstractBeing a classic monogenic disease, 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 effective drug. We thus explored the expression of human (h)CFTR encoded by hCFTRcmRNAin vitro, analyzed by flow cytometry and Western Blot and its function with a YFP assay. Very similar effects could be observedin vivowhen hCFTRcmRNA was assembled with Chitosan-coated PLGA to nanoparticles (NPs) and intratracheally (i.t.) or intravenously (i.v) injected, the latter one as an alternative administration route to circumvent the clogged airways of CF patients. This significantly improved lung function, which suggests that hCFTRcmRNA-NPs are a promising therapeutic option for CF patients independent of theirCFTRgenotype.