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In vivo genome editing using nuclease-encoding mRNA corrects SP-B deficiency

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Figure 1: nec-mRNA cleaves the SP-B cassette, induces HDR in vitro and is expressed in lung cells in vivo.
Figure 2: Rescue of SP-B deficient mice by in vivo gene manipulation.

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (DFG KO 4258/2-1, to M.S.D.K and L.E.M.), fortüne grant (no. 1980-0-0, to M.S.D.K.), by the European Respiratory Society (Maurizio Vignola Award, to M.S.D.K.), in part by the Mukoviszidose e.V. (S03/12 to M.S.D.K.), in part by the Deutsche Forschungsgemeinschaft Emmy Noether Programme (HA 5274/3-1, to D. H.), in part by the Interfaculty Center for Pharmacogenomics and Drug Research (ICEPHA Twinning Grant 22-0-0 to S.B.-H.) and in part by DFG (to B.N., S.B.-H. and M.G. (970/8.1)). Site-specific nucleases were kindly provided by Sangamo BioSciences. Thank you to D. Fraude for excellent illustration support. Primary antibody against SP-B was kindly provided by M.G.

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Author notes

  1. Azita J Mahiny, Alexander Dewerth and Lauren E Mays: These authors contributed equally to the work.

Authors and Affiliations

  1. Department of Pediatrics I–Pediatric Infectiology and Immunology, Translational Genomics and Gene Therapy, University of Tübingen, Tübingen, Germany

    Azita J Mahiny, Alexander Dewerth, Lauren E Mays, Mohammed Alkhaled, Jennifer Rottenberger, Darina M Brosch, Philipp Reautschnig, Pacharapan Surapolchai, Franziska Zeyer, Melanie Carevic, Martina Bakele, Rupert Handgretinger, Dominik Hartl & Michael S D Kormann

  2. Department of Pharmacology and Experimental Therapy, University of Tübingen, Tübingen, Germany

    Benedikt Mothes, Bernd Nürnberg & Sandra Beer-Hammer

  3. ICePha, University of Tübingen, Tübingen, Germany

    Benedikt Mothes & Matthias Schwab

  4. Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research (HZI), Saarbrücken, Germany

    Emad Malaeksefat, Brigitta Loretz & Claus-Michael Lehr

  5. Department of Pediatric Pulmonology, Dr. von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany

    Andrea Schams & Matthias Griese

  6. Member of the German Center for Lung Research (DZL), Munich, Germany

    Andrea Schams & Matthias Griese

  7. Department of Clinical Pharmacology, University of Tübingen, Tübingen, Germany

    Matthias Schwab

  8. Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

    Matthias Schwab

  9. Department of Pharmacy, Saarland University, Saarbrücken, Germany

    Claus-Michael Lehr

Authors
  1. Azita J Mahiny
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  2. Alexander Dewerth
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  23. Michael S D Kormann
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Contributions

M.S.D.K. designed research, and together with A.J.M. and A.D., carried out experiments and analyzed data. B.M. performed the isolated lung experiments, and together with S.B.-H., participated in the interpretation and analysis of the data, with S.B.-H. and B.N. providing administrative and technical support. M.A., E.M., B.L., L.E.M., J.R., D.M.B., P.R., P.S., F.Z., A.S., M.C. and M.B. conceived and performed experiments. M.G., M.S., R.H., D.H. and C.-M.L. provided materials. M.S.D.K. and L.E.M. wrote the manuscript. All authors discussed results and implications, commented on or edited parts of the manuscript.

Corresponding authors

Correspondence to Claus-Michael Lehr or Michael S D Kormann.

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Competing interests

M.S.D.K. and L.E.M. are listed as co-inventors on a patent application related to this work. M.S.D.K. is an inventor on a patent licensed to the biopharmaceutical company Ethris GmbH.

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Supplementary Figures 1–22, Supplementary Sequences and Supplementary Discussion (PDF 48690 kb)

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Mahiny, A., Dewerth, A., Mays, L. et al. In vivo genome editing using nuclease-encoding mRNA corrects SP-B deficiency. Nat Biotechnol 33, 584–586 (2015). https://doi.org/10.1038/nbt.3241

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