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

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

doi:10.1016/j.omtn.2025.102467

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

Mol Ther Nucleic Acids. 2025 Jan 29;36(1):102467. doi: 10.1016/j.omtn.2025.102467. eCollection 2025 Mar 11.

Authors

Yuta Suzuki¹, Takayuki Miyazaki¹, Yoko Ida², Tatsuya Suzuki^{3

4}, Yumi Itoh^{3

4}, Shuto Nakao³, Keita Kondo¹, Kenji Kubara¹, Keisuke Nishioka⁵, Hiroki Muto¹, Ryuji Watari¹, Toshifumi Hirayama², Dai Kakiuchi¹, Shinya Sato¹, Satoshi Inoue¹, Yoshifumi Uemoto¹, Yohei Mukai², Atsushi Hoshino⁶, Toru Okamoto^{3

4}, Junji Matsui¹

Affiliations

¹ Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki 300-2635, Japan.
² Kobe Research Laboratories, Eisai Co., Ltd., Kobe 650-0047, Japan.
³ Department of Microbiology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
⁴ Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
⁵ Department of Infectious Diseases, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
⁶ Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.

Abstract

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.

Keywords: ACE2 decoy; COVID-19; MT: Oligonucleotides: Therapies and Applications; SARS-CoV-2; escape mutation; lipid nanoparticles; mRNA delivery; mRNA therapeutics.