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 Stands 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 Bottoms for ACE2-based treatment of liver and lung fibrosis to be tested in fibrotic disease models.