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Publications

Journal Article Epublish

PubMed: 40276779 DOI: 10.1016/j.omtm.2025.101459

Engineered ACE2 decoy in dry powder form for inhalation: A novel therapy for SARS-CoV-2 variants.

Mol Ther Methods Clin Dev 33(2):101459

Authors: Takaaki Ito, Tatsuya Suzuki, Yusuke Sakai, Keisuke Nishioka, Yumi Itoh, Kentarou Sakamoto, Nariko Ikemura, Satoaki Matoba, Yasunari Kanda, Junichi Takagi, Toru Okamoto, Kohei Tahara, Atsushi Hoshino

Affiliations

  • Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
  • Department of Microbiology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
  • Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
  • Department of Pathology, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.
  • Department of Infectious Diseases, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
  • Laboratory for Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Osaka 565-0871, Japan.
  • Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
  • Division of Pharmacology, National Institute of Health Sciences, Kanagawa 210-9501, Japan.
  • Center for Infectious Disease Education and Research, Osaka University, Osaka 565-0871, Japan.
  • Laboratory of Nanofiber Technology, Gifu Pharmaceutical University, Gifu 501-1196, Japan.

Abstract

The persistent threat of SARS-CoV-2 and the emergence of new variants has prompted the development of a novel, easily administered modality that can overcome viral mutations. The engineered ACE2 decoy shows neutralizing activity comparable to monoclonal antibodies and is broadly effective against SARS-CoV-2 variants and ACE2-utilizing sarbecoviruses. In addition to intravenous administration, this decoy has shown antiviral efficacy through nebulized aerosol inhalation in murine and primate models, offering a dose-sparing advantage. Clinically, dry powder formulation is ideal for convenience and storage but poses challenges for protein biologics. This study developed a freeze-dried spray formulation of the ACE2 decoy for inhalation. The trehalose and leucine-based excipient maintained neutralizing activity and prevented aggregate formation. The dry powder showed aerodynamic distribution from bronchi to alveoli, aiding protection against SARS-CoV-2 infections. Neutralizing activity, structural stability, and powder dispersibility were preserved after 6 months of storage. In a mouse model of SARS-CoV-2 infection, significant reductions in viral replication and lung pathology were observed with intratracheal administration 24 h post-infection. The ACE2 decoy retained activity against recent JN.1 and current KP.3 strains, confirming its robust efficacy against viral mutations. This ACE2 decoy powder inhalant is a self-administered, next-generation treatment addressing the ongoing immune-evading evolution of SARS-CoV-2.

MeSH

Sars-Cov-2, Powders, Inhalation, Covid-19, Therapeutics, Severe Acute Respiratory Syndrome-Related Coronavirus, Mutation, Infections