Translation of angiotensin-converting enzyme 2 upon liver-and lung-targeted delivery of optimized chemically modified mRNA
Open accessAbstract
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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Compared with other organs, a stronger luciferase signal in the lungs indicated pulmonary specificity of C12-(2-3-2) oligoalkylamine lipid micelle nanoparticles.
“Compared with other organs, the stronger luciferase signal in the lungs indicated the pulmonary specificity.”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [193]
After 6 hours, obvious accumulation of ACE2 mRNA and proteins was observed in the lungs after i.v. delivery by lung-targeted nanoparticles.
“After 6 hours, obvious accumulation of ACE2 mRNA and proteins were observed in the lungs.[192, 193]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [193]
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- Authors
- 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.
- Affiliations
- Ethris (Germany) (DE)
- Helmholtz Munich (DE)
- Technical University of Munich (DE)
- Fraunhofer Institute for Toxicology and Experimental Medicine (DE)
- Corresponding author
- Rudolph, Carsten
- Kubisch-Dohmen, Rebekka
- ORCID
- Venue
- Molecular Therapy — Nucleic Acids
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 7
- Pages
- 350-365
- ISSN
- 2162-2531 (ISSN-L)
- PMC
- PMC5423349
- OpenAlex
- W2607297673
- Cited by
- 69
- References
- 76
- Citations by year
- 2025: 5 · 2024: 5 · 2023: 7 · 2022: 13 · 2021: 11 · 2020: 8 · 2019: 8 · 2018: 10 · 2017: 2
- FWCI
- 3.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Therapy — Nucleic Acids (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Site cant be reached (submittedVersion, cc-by-nc-nd)
- Fraunhofer-Publica (Fraunhofer-Gesellschaft) (submittedVersion)
- Funders
- Bundesministerium für Bildung und Forschung
- Helmholtz Zentrum München
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- angiotensin-converting enzyme 2, chemically modified mRNA, liver fibrosis, pulmonary fibrosis, lipid nanoparticles
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