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

AKM Ashiqul Haque, Alexander Dewerth, Justin S. Antony, Joachim Riethmüller, Ngadhnjim Latifi, Hanzey Yasar, Petra Weinmann, View ORCID ProfileNicoletta Pedemonte, Elvira Sondo, Julie Laval, Patrick Schlegel, Christian Seitz, Brigitta Loretz, Claus-Michael Lehr, Rupert Handgretinger, View ORCID ProfileMichael S. D. Kormann
doi: https://doi.org/10.1101/202853
AKM Ashiqul Haque
1Department of Pediatrics I - Pediatric Infectiology and Immunology, Translational Genomics and Gene Therapy, University of Tuebingen, Germany
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Alexander Dewerth
1Department of Pediatrics I - Pediatric Infectiology and Immunology, Translational Genomics and Gene Therapy, University of Tuebingen, Germany
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Justin S. Antony
1Department of Pediatrics I - Pediatric Infectiology and Immunology, Translational Genomics and Gene Therapy, University of Tuebingen, Germany
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Joachim Riethmüller
6Department of Pediatrics I - Cystic Fibrosis Ambulance
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Ngadhnjim Latifi
1Department of Pediatrics I - Pediatric Infectiology and Immunology, Translational Genomics and Gene Therapy, University of Tuebingen, Germany
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Hanzey Yasar
4Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research (HZI), Saarbruecken, Germany
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Petra Weinmann
1Department of Pediatrics I - Pediatric Infectiology and Immunology, Translational Genomics and Gene Therapy, University of Tuebingen, Germany
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Nicoletta Pedemonte
3U.O.C. Genetica Medica, Istituto Giannina Gaslini, Genova, Italy
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  • ORCID record for Nicoletta Pedemonte
Elvira Sondo
3U.O.C. Genetica Medica, Istituto Giannina Gaslini, Genova, Italy
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Julie Laval
2Department of Pediatrics I - Immunology and Pneumology/Cystic fibrosis, Department of Pediatrics I, University of Tübingen.
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Patrick Schlegel
1Department of Pediatrics I - Pediatric Infectiology and Immunology, Translational Genomics and Gene Therapy, University of Tuebingen, Germany
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Christian Seitz
1Department of Pediatrics I - Pediatric Infectiology and Immunology, Translational Genomics and Gene Therapy, University of Tuebingen, Germany
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Brigitta Loretz
4Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research (HZI), Saarbruecken, Germany
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Claus-Michael Lehr
4Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research (HZI), Saarbruecken, Germany
5Department of Pharmacy, Saarland University, Saarbruecken, Germany
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Rupert Handgretinger
1Department of Pediatrics I - Pediatric Infectiology and Immunology, Translational Genomics and Gene Therapy, University of Tuebingen, Germany
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Michael S. D. Kormann
1Department of Pediatrics I - Pediatric Infectiology and Immunology, Translational Genomics and Gene Therapy, University of Tuebingen, Germany
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  • ORCID record for Michael S. D. Kormann
  • For correspondence: michael.kormann@med.uni-tuebingen.de
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Abstract

Being 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 hCFTR cmRNA in vitro, analyzed by flow cytometry and Western Blot and its function with a YFP assay. Very similar effects could be observed in vivo when hCFTR cmRNA 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 hCFTR cmRNA-NPs are a promising therapeutic option for CF patients independent of their CFTR genotype.

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Posted October 13, 2017.
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Modified hCFTR mRNA restores normal lung function in a mouse model of cystic fibrosis
AKM Ashiqul Haque, Alexander Dewerth, Justin S. Antony, Joachim Riethmüller, Ngadhnjim Latifi, Hanzey Yasar, Petra Weinmann, Nicoletta Pedemonte, Elvira Sondo, Julie Laval, Patrick Schlegel, Christian Seitz, Brigitta Loretz, Claus-Michael Lehr, Rupert Handgretinger, Michael S. D. Kormann
bioRxiv 202853; doi: https://doi.org/10.1101/202853
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Modified hCFTR mRNA restores normal lung function in a mouse model of cystic fibrosis
AKM Ashiqul Haque, Alexander Dewerth, Justin S. Antony, Joachim Riethmüller, Ngadhnjim Latifi, Hanzey Yasar, Petra Weinmann, Nicoletta Pedemonte, Elvira Sondo, Julie Laval, Patrick Schlegel, Christian Seitz, Brigitta Loretz, Claus-Michael Lehr, Rupert Handgretinger, Michael S. D. Kormann
bioRxiv 202853; doi: https://doi.org/10.1101/202853

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