Translation of Angiotensin-Converting Enzyme 2 upon Liver- and Lung-Targeted Delivery of Optimized Chemically Modified mRNA

• Main Authors: Eva Schrom (Author), Maja Huber (Author), Manish Aneja (Author), Christian Dohmen (Author), Daniela Emrich (Author), Johannes Geiger (Author), Günther Hasenpusch (Author), Annika Herrmann-Janson (Author), Verena Kretzschmann (Author), Olga Mykhailyk (Author), Tamara Pasewald (Author), Prajakta Oak (Author), Anne Hilgendorff (Author), Dirk Wohlleber (Author), Heinz-Gerd Hoymann (Author), Dirk Schaudien (Author), Christian Plank (Author), Carsten Rudolph (Author), Rebekka Kubisch-Dohmen (Author)
• Format: Book
• Published: Elsevier, 2017-06-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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.

Item Description

2162-2531
10.1016/j.omtn.2017.04.006