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10 05, 2023;30 (10): 1315-1330.e10.

Complement factor D targeting protects endotheliopathy in organoid and monkey models of COVID-19.

Eri Kawakami, Norikazu Saiki, Yosuke Yoneyama, Chiharu Moriya, Mari Maezawa, Shuntaro Kawamura, Akiko Kinebuchi, Tamaki Kono, Masaaki Funata, Ayaka Sakoda, Shigeru Kondo, Takeshi Ebihara, Hisatake Matsumoto, Yuki Togami, Hiroshi Ogura, Fuminori Sugihara, Daisuke Okuzaki, Takashi Kojima, Sayaka Deguchi, Sebastien Vallee, Susan McQuade, Rizwana Islam, Madhusudan Natarajan, Hirohito Ishigaki, Misako Nakayama, Cong Thanh Nguyen, Yoshinori Kitagawa, Yunheng Wu, Kensaku Mori, Takayuki Hishiki, Tomohiko Takasaki, Yasushi Itoh, Kazuo Takayama, Yasunori Nio, Takanori Takebe
Author Information
  1. Eri Kawakami: T-CiRA Discovery & Innovation, Takeda Pharmaceutical Company Ltd, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan; Organoid Medicine Project, T-CiRA Joint Program, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
  2. Norikazu Saiki: Institute of Research, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Organoid Medicine Project, T-CiRA Joint Program, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
  3. Yosuke Yoneyama: Institute of Research, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
  4. Chiharu Moriya: Institute of Research, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
  5. Mari Maezawa: Institute of Research, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
  6. Shuntaro Kawamura: Institute of Research, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
  7. Akiko Kinebuchi: Institute of Research, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
  8. Tamaki Kono: T-CiRA Discovery & Innovation, Takeda Pharmaceutical Company Ltd, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan; Organoid Medicine Project, T-CiRA Joint Program, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
  9. Masaaki Funata: T-CiRA Discovery & Innovation, Takeda Pharmaceutical Company Ltd, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan; Organoid Medicine Project, T-CiRA Joint Program, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
  10. Ayaka Sakoda: T-CiRA Discovery & Innovation, Takeda Pharmaceutical Company Ltd, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
  11. Shigeru Kondo: T-CiRA Discovery & Innovation, Takeda Pharmaceutical Company Ltd, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
  12. Takeshi Ebihara: Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, 2-15, Yamada-oka, Suita, Osaka 565-0871, Japan.
  13. Hisatake Matsumoto: Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, 2-15, Yamada-oka, Suita, Osaka 565-0871, Japan.
  14. Yuki Togami: Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, 2-15, Yamada-oka, Suita, Osaka 565-0871, Japan.
  15. Hiroshi Ogura: Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, 2-15, Yamada-oka, Suita, Osaka 565-0871, Japan.
  16. Fuminori Sugihara: Core Instrumentation Facility, Immunology Frontier Research Center and Research Institute for Microbial Diseases, Osaka University, 3-3-1, Yamada-oka, Suita, Osaka 565-0871, Japan.
  17. Daisuke Okuzaki: Genome Information Research Center, Research Institute for Microbial Disease, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
  18. Takashi Kojima: Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, 2-15, Yamada-oka, Suita, Osaka 565-0871, Japan.
  19. Sayaka Deguchi: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
  20. Sebastien Vallee: Rare Disease DDU, Takeda Pharmaceutical Company Ltd, 125 Binney Street, Cambridge, MA 02139, USA.
  21. Susan McQuade: Rare Disease DDU, Takeda Pharmaceutical Company Ltd, 125 Binney Street, Cambridge, MA 02139, USA; BPS Biosciences Inc., 6405 Mira Mesa Blvd. Suite 100, San Diego, CA 92121, USA.
  22. Rizwana Islam: Rare Disease DDU, Takeda Pharmaceutical Company Ltd, 125 Binney Street, Cambridge, MA 02139, USA.
  23. Madhusudan Natarajan: Rare Disease DDU, Takeda Pharmaceutical Company Ltd, 125 Binney Street, Cambridge, MA 02139, USA.
  24. Hirohito Ishigaki: Department of Pathology, Shiga University of Medical Science, Setatsukinowa, Otsu, Shiga 520-2192, Japan.
  25. Misako Nakayama: Department of Pathology, Shiga University of Medical Science, Setatsukinowa, Otsu, Shiga 520-2192, Japan.
  26. Cong Thanh Nguyen: Department of Pathology, Shiga University of Medical Science, Setatsukinowa, Otsu, Shiga 520-2192, Japan.
  27. Yoshinori Kitagawa: Department of Pathology, Shiga University of Medical Science, Setatsukinowa, Otsu, Shiga 520-2192, Japan.
  28. Yunheng Wu: Graduate School of Informatics, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
  29. Kensaku Mori: Graduate School of Informatics, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan; Information Technology Center, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan; Research Center for Medical Bigdata, National Institute of Informatics, Tokyo 100-0003, Japan.
  30. Takayuki Hishiki: Kanagawa Prefectural Institute of Public Health, 1-3-1, Shimomachiya, Chigasaki, Kanagawa 253-0087, Japan; Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
  31. Tomohiko Takasaki: Kanagawa Prefectural Institute of Public Health, 1-3-1, Shimomachiya, Chigasaki, Kanagawa 253-0087, Japan; Advanced Technology and Development Division, BML, INC, 1361-1, Matoba, Kawagoe-shi, Saitama 350-1101, Japan.
  32. Yasushi Itoh: Department of Pathology, Shiga University of Medical Science, Setatsukinowa, Otsu, Shiga 520-2192, Japan.
  33. Kazuo Takayama: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
  34. Yasunori Nio: T-CiRA Discovery & Innovation, Takeda Pharmaceutical Company Ltd, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan; Organoid Medicine Project, T-CiRA Joint Program, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: ynioh0506@gmail.com.
  35. Takanori Takebe: Institute of Research, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Organoid Medicine Project, T-CiRA Joint Program, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan; Division of Gastroenterology, Hepatology and Nutrition & Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA; The Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA; Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA; Communication Design Center, Advanced Medical Research Center, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan; Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe) and Department of Genome Biology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan. Electronic address: takanori.takebe@cchmc.org.
PMID: 37802037 DOI: 10.1016/j.stem.2023.09.001

Abstract

COVID-19 is linked to endotheliopathy and coagulopathy, which can result in multi-organ failure. The mechanisms causing endothelial damage due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain elusive. Here, we developed an infection-competent human vascular organoid from pluripotent stem cells for modeling endotheliopathy. Longitudinal serum proteome analysis identified aberrant complement signature in critically ill patients driven by the amplification cycle regulated by complement factor B and D (CFD). This deviant complement pattern initiates endothelial damage, neutrophil activation, and thrombosis specific to organoid-derived human blood vessels, as verified through intravital imaging. We examined a new long-acting, pH-sensitive (acid-switched) antibody targeting CFD. In both human and macaque COVID-19 models, this long-acting anti-CFD monoclonal antibody mitigated abnormal complement activation, protected endothelial cells, and curtailed the innate immune response post-viral exposure. Collectively, our findings suggest that the complement alternative pathway exacerbates endothelial injury and inflammation. This underscores the potential of CFD-targeted therapeutics against severe viral-induced inflammathrombotic outcomes.

Keywords

CFD SARS-CoV-2 acid-switch half-life extended antibody complement cynomolgus macaque endotheliopathy iPSC thrombopathy vascular organoid

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Grants

  1. DP2 DK128799/NIDDK NIH HHS
  2. R01 DK135478/NIDDK NIH HHS
  3. UH3 DK119982/NIDDK NIH HHS
  4. P30 DK078392/NIDDK NIH HHS

MeSH Term

Animals
Humans
COVID-19
SARS-CoV-2
Complement Factor D
Endothelial Cells
Haplorhini

Chemicals

Complement Factor D
Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

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