tetano
Editor, Senior Moderator
Mol Ther Nucleic Acids
. 2025 Jan 29;36(1):102467.
doi: 10.1016/j.omtn.2025.102467. eCollection 2025 Mar 11. In vivo production of engineered ACE2 decoy protects lungs from SARS-CoV-2 infection
Yuta Suzuki[SUP] 1 [/SUP], Takayuki Miyazaki[SUP] 1 [/SUP], Yoko Ida[SUP] 2 [/SUP], Tatsuya Suzuki[SUP] 3 4 [/SUP], Yumi Itoh[SUP] 3 4 [/SUP], Shuto Nakao[SUP] 3 [/SUP], Keita Kondo[SUP] 1 [/SUP], Kenji Kubara[SUP] 1 [/SUP], Keisuke Nishioka[SUP] 5 [/SUP], Hiroki Muto[SUP] 1 [/SUP], Ryuji Watari[SUP] 1 [/SUP], Toshifumi Hirayama[SUP] 2 [/SUP], Dai Kakiuchi[SUP] 1 [/SUP], Shinya Sato[SUP] 1 [/SUP], Satoshi Inoue[SUP] 1 [/SUP], Yoshifumi Uemoto[SUP] 1 [/SUP], Yohei Mukai[SUP] 2 [/SUP], Atsushi Hoshino[SUP] 6 [/SUP], Toru Okamoto[SUP] 3 4 [/SUP], Junji Matsui[SUP] 1 [/SUP]
Affiliations
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.
. 2025 Jan 29;36(1):102467.
doi: 10.1016/j.omtn.2025.102467. eCollection 2025 Mar 11. In vivo production of engineered ACE2 decoy protects lungs from SARS-CoV-2 infection
Yuta Suzuki[SUP] 1 [/SUP], Takayuki Miyazaki[SUP] 1 [/SUP], Yoko Ida[SUP] 2 [/SUP], Tatsuya Suzuki[SUP] 3 4 [/SUP], Yumi Itoh[SUP] 3 4 [/SUP], Shuto Nakao[SUP] 3 [/SUP], Keita Kondo[SUP] 1 [/SUP], Kenji Kubara[SUP] 1 [/SUP], Keisuke Nishioka[SUP] 5 [/SUP], Hiroki Muto[SUP] 1 [/SUP], Ryuji Watari[SUP] 1 [/SUP], Toshifumi Hirayama[SUP] 2 [/SUP], Dai Kakiuchi[SUP] 1 [/SUP], Shinya Sato[SUP] 1 [/SUP], Satoshi Inoue[SUP] 1 [/SUP], Yoshifumi Uemoto[SUP] 1 [/SUP], Yohei Mukai[SUP] 2 [/SUP], Atsushi Hoshino[SUP] 6 [/SUP], Toru Okamoto[SUP] 3 4 [/SUP], Junji Matsui[SUP] 1 [/SUP]
Affiliations
- PMID: 40027884
- PMCID: PMC11869860
- DOI: 10.1016/j.omtn.2025.102467
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.