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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Elsevier
2025-03-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253125000216 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yuta Suzuki |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-217382a69710467aac79c6eaca7bd1ac |
| institution | Kabale University |
| issn | 2162-2531 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj-art-217382a69710467aac79c6eaca7bd1ac2025-02-12T05:30:59ZengElsevierMolecular Therapy: Nucleic Acids2162-25312025-03-01361102467In vivo production of engineered ACE2 decoy protects lungs from SARS-CoV-2 infectionYuta Suzuki0Takayuki Miyazaki1Yoko Ida2Tatsuya Suzuki3Yumi Itoh4Shuto Nakao5Keita Kondo6Kenji Kubara7Keisuke Nishioka8Hiroki Muto9Ryuji Watari10Toshifumi Hirayama11Dai Kakiuchi12Shinya Sato13Satoshi Inoue14Yoshifumi Uemoto15Yohei Mukai16Atsushi Hoshino17Toru Okamoto18Junji Matsui19Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki 300-2635, Japan; Corresponding author: Yuta Suzuki, Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki 300-2635, Japan.Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki 300-2635, JapanKobe Research Laboratories, Eisai Co., Ltd., Kobe 650-0047, JapanDepartment of Microbiology, Juntendo University School of Medicine, Tokyo 113-8421, Japan; Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, JapanDepartment of Microbiology, Juntendo University School of Medicine, Tokyo 113-8421, Japan; Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, JapanDepartment of Microbiology, Juntendo University School of Medicine, Tokyo 113-8421, JapanTsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki 300-2635, JapanTsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki 300-2635, JapanDepartment of Infectious Diseases, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, JapanTsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki 300-2635, JapanTsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki 300-2635, JapanKobe Research Laboratories, Eisai Co., Ltd., Kobe 650-0047, JapanTsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki 300-2635, JapanTsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki 300-2635, JapanTsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki 300-2635, JapanTsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki 300-2635, JapanKobe Research Laboratories, Eisai Co., Ltd., Kobe 650-0047, JapanDepartment of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan; Corresponding author: Atsushi Hoshino, Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.Department of Microbiology, Juntendo University School of Medicine, Tokyo 113-8421, Japan; Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan; Corresponding author: Toru Okamoto, Department of Microbiology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki 300-2635, JapanSevere 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.http://www.sciencedirect.com/science/article/pii/S2162253125000216MT: Oligonucleotides: Therapies and ApplicationsmRNA therapeuticsmRNA deliveryACE2 decoyescape mutationlipid nanoparticles |
| spellingShingle | 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 In vivo production of engineered ACE2 decoy protects lungs from SARS-CoV-2 infection Molecular Therapy: Nucleic Acids MT: Oligonucleotides: Therapies and Applications mRNA therapeutics mRNA delivery ACE2 decoy escape mutation lipid nanoparticles |
| title | In vivo production of engineered ACE2 decoy protects lungs from SARS-CoV-2 infection |
| title_full | In vivo production of engineered ACE2 decoy protects lungs from SARS-CoV-2 infection |
| title_fullStr | In vivo production of engineered ACE2 decoy protects lungs from SARS-CoV-2 infection |
| title_full_unstemmed | In vivo production of engineered ACE2 decoy protects lungs from SARS-CoV-2 infection |
| title_short | In vivo production of engineered ACE2 decoy protects lungs from SARS-CoV-2 infection |
| title_sort | in vivo production of engineered ace2 decoy protects lungs from sars cov 2 infection |
| topic | MT: Oligonucleotides: Therapies and Applications mRNA therapeutics mRNA delivery ACE2 decoy escape mutation lipid nanoparticles |
| url | http://www.sciencedirect.com/science/article/pii/S2162253125000216 |
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