Schrom Eva, Huber Maja, Aneja Manish, Dohmen Christian, Emrich Daniela, Geiger Johannes, Hasenpusch Günther, Herrmann-Janson Annika, Kretzschmann Verena, Mykhailyk Olga, Pasewald Tamara, Oak Prajakta, Hilgendorff Anne, Wohlleber Dirk, Hoymann Heinz-Gerd, Schaudien Dirk, Plank Christian, Rudolph Carsten, Kubisch-Dohmen Rebekka
Department of Pediatrics, LMU Munich, 80802 Munich, Germany; Ethris GmbH, 82152 Planegg, Germany.
Ethris GmbH, 82152 Planegg, Germany.
Mol Ther Nucleic Acids. 2017 Jun 16;7:350-365. doi: 10.1016/j.omtn.2017.04.006. Epub 2017 Apr 13.
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.
生活方式和环境条件的变化导致肝肺纤维化的患病率不断上升，且两者预后均较差。在实验性肝肺纤维化中，重组血管紧张素转换酶2（ACE2）蛋白给药已报告有良好结果。然而，ACE2的全部潜力可能通过膜锚定形式的局部翻译来实现。为此，我们采用了最新的RNA技术进行肝肺靶向性ACE2翻译。我们在体外证明，用化学修饰的信使RNA（cmRNA）转染ACE2可导致完全成熟的膜锚定ACE2蛋白的强劲翻译。第二步，我们设计了八个修饰的ACE2 cmRNA序列，并确定了一个用于体内应用的先导序列。最后，将这种ACE2 cmRNA配制在特制的类脂质纳米颗粒和脂质纳米颗粒中，分别导致大量ACE2蛋白的肝肺靶向性翻译。总之，我们提供的证据表明，RNA转录物疗法（RTT）是一种有前景的基于ACE2治疗肝肺纤维化的方法，有待在纤维化疾病模型中进行测试。
