translation of angiotensin-converting enzyme 2 upon liver- and lung-targeted delivery of optimized chemically modified mrna
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2017
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Abstract
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.
| Reference Key |
schrom2017moleculartranslation
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| Authors | ;Eva Schrom;Maja Huber;Manish Aneja;Christian Dohmen;Daniela Emrich;Johannes Geiger;Günther Hasenpusch;Annika Herrmann-Janson;Verena Kretzschmann;Olga Mykhailyk;Tamara Pasewald;Prajakta Oak;Anne Hilgendorff;Dirk Wohlleber;Heinz-Gerd Hoymann;Dirk Schaudien;Christian Plank;Carsten Rudolph;Rebekka Kubisch-Dohmen |
| Journal | coordination chemistry reviews |
| Year | 2017 |
| DOI |
10.1016/j.omtn.2017.04.006
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| URL | |
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