In vivo production of engineered ACE2 decoy protects lungs from SARS-CoV-2 infection

In vivo production of engineered ACE2 decoy protects lungs from SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants repeatedly evade the immune system within short periods. Thus, next-generation therapeutics that are resistant to mutations and can be rapidly supplied to individuals in an emergency are required. Here, we designed an mRNA encodin...

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Main Authors: Yuta Suzuki, Takayuki Miyazaki, Yoko Ida, Tatsuya Suzuki, Yumi Itoh, Shuto Nakao, Keita Kondo, Kenji Kubara, Keisuke Nishioka, Hiroki Muto, Ryuji Watari, Toshifumi Hirayama, Dai Kakiuchi, Shinya Sato, Satoshi Inoue, Yoshifumi Uemoto, Yohei Mukai, Atsushi Hoshino, Toru Okamoto, Junji Matsui
Format: Article
Language:English
Published: Elsevier 2025-03-01
Series:Molecular Therapy: Nucleic Acids
Subjects:
MT: Oligonucleotides: Therapies and Applications
mRNA therapeutics
mRNA delivery
ACE2 decoy
escape mutation
lipid nanoparticles
Online Access:http://www.sciencedirect.com/science/article/pii/S2162253125000216
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Summary:Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants repeatedly evade the immune system within short periods. Thus, next-generation therapeutics that are resistant to mutations and can be rapidly supplied to individuals in an emergency are required. Here, we designed an mRNA encoding an engineered angiotensin-converting enzyme 2 (ACE2) decoy, 3N39v4, composed of high-affinity ACE2 and a human immunoglobulin G Fc domain. The 3N39v4-encoded mRNA was encapsulated in lipid nanoparticles for efficient in vivo delivery. Systemic delivery of mRNA in mice resulted in a dose-dependent expression of 3N39v4 in plasma (20–261 μg/mL at 1–10 mg/kg) with sufficient tolerability. An improved pharmacokinetic profile of the produced protein was compared to injection of the 3N39v4 protein. In vivo-expressed 3N39v4 exhibited broad neutralization against nine SARS-CoV-2 variants and other sarbecoviruses, including the currently circulating Omicron subvariants JN.1 and BA.2.86. A single intravenous injection of 3N39v4-encoded mRNA resulted in a robust, dose-dependent improvement in the outcomes of mice infected with SARS-CoV-2. The mRNA treatment in monkeys produced 3N39v4 in sera, which inhibited the replication of the authentic viruses. The rapid development of mRNA drugs highlights the potential of mRNA-encoded ACE2 decoys in emergencies to combat diverse SARS-CoV-2 variants, including future variants.
ISSN:2162-2531

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