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Translation of angiotensin-converting enzyme 2 upon liver- and lung-targeted delivery of optimized chemically modified mRNA

: Schrom, E.; Huber, M.; Aneja, M.; Dohmen, C.; Emrich, D.; Geiger, J.; Hasenpusch, G.; Herrmann-Janson, A.; Kretzschmann, V.; Mykhailyk, O.; Pasewald, T.; Oak, P.; Hilgendorff, A.; Wohlleber, D.; Hoymann, H.-G.; Schaudien, D.; Plank, C.; Rudolph, C.; Kubisch-Dohmen, R.

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Molecular therapy. Nucleic Acids 7 (2017), pp.350-365
ISSN: 2162-2531
Journal Article, Electronic Publication
Fraunhofer ITEM ()

Changes in lifestyle and environmental conditions give rise to an increasing prevalence of liver and lung fibrosis, and both have a poor prognosis. Promising results have been reported for recombinant angiotensin-converting enzyme 2 (ACE2) protein administration in experimental liver and lung fibrosis. However, the full potential of ACE2 may be achieved by localized translation of a membrane-anchored form. For this purpose, we advanced the latest RNA technology for liver- and lung-targeted ACE2 translation. We demonstrated in vitro that transfection with ACE2 chemically modified messenger RNA (cmRNA) leads to robust translation of fully matured, membrane-anchored ACE2 protein. In a second step, we designed eight modified ACE2 cmRNA sequences and identified a lead sequence for in vivo application. Finally, formulation of this ACE2 cmRNA in tailor-made lipidoid nanoparticles and in lipid nanoparticles led to liver- and lung-targeted translation of significant amounts of ACE2 protein, respectively. In summary, we provide evidence that RNA transcript therapy (RTT) is a promising approach for ACE2-based treatment of liver and lung fibrosis to be tested in fibrotic disease models.