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Schrom, E.* ; Huber, M.* ; Aneja, M.K.* ; 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.* ; Schaudien, D.* ; Plank, C.* ; Rudolph, C.* ; Kubisch-Dohmen, R.*

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

Mol. Ther. Nucleic Acids 7, 350-365 (2017)

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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.

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