Chemically Modified HCFTR MRNAs Recuperate Lung Function in a Mouse Model of Cystic Fibrosis

Overview

Journal Sci Rep

Specialty Science

Date 2018 Nov 15

PMID 30425265

Citations 36

Authors

A K M Ashiqul Haque

Alexander Dewerth

Justin S Antony

Joachim Riethmuller

Georg R Schweizer

Petra Weinmann

Ngadhnjim Latifi

Hanzey Yasar

Nicoletta Pedemonte

Elvira Sondo

Brian Weidensee

Anjali Ralhan

Julie Laval

Patrick Schlegel

Christian Seitz

Brigitta Loretz

Claus-Michael Lehr

Rupert Handgretinger

Michael S D Kormann

Affiliations

Soon will be listed here.

Abstract

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 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 in vivo after intratracheal (i.t.) or intravenous (i.v.) injection of the assembled cmRNA 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 was quantified by hCFTR ELISA, and cmRNA values were assessed by RT-qPCR. Thereby, we observed a significant improvement of lung function, especially in regards to FEV, suggesting NP-cmRNA as promising therapeutic option for CF patients independent of their CFTR genotype.

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