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Journal Article Epublish 25 citations

PubMed: 35160081 DOI: 10.3390/jcm11030630

Plasma-Derived Hemopexin as a Candidate Therapeutic Agent for Acute Vaso-Occlusion in Sickle Cell Disease: Preclinical Evidence.

J Clin Med 11(3)

Authors: Thomas Gentinetta, John D Belcher, Valérie Brügger-Verdon, Jacqueline Adam, Tanja Ruthsatz, Joseph Bain, Daniel Schu, Lisa Ventrici, Monika Edler, Hadi Lioe, Kalpeshkumar Patel, Chunsheng Chen, Julia Nguyen, Fuad Abdulla, Ping Zhang, Andreas Wassmer, Meena Jain, Marcel Mischnik, Matthias Pelzing, Kirstee Martin, Roslyn Davis, Svetlana Didichenko, Alexander Schaub, Nathan Brinkman, Eva Herzog, Adrian Zürcher, Gregory M Vercellotti, Gregory J Kato, Gerald Höbarth

Affiliations

  • Research and Development, CSL Behring AG, 3014 Bern, Switzerland.
  • Division of Hematology, Oncology and Transplantation, Vascular Biology Center, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
  • CSL Behring Innovation GmbH, 35041 Marburg, Germany.
  • Bio21 Institute, CSL Ltd. Parkville, VIC 3052, Australia.
  • Research and Development, CSL Behring, King of Prussia, PA 19406, USA.
  • Research and Development, CSL Behring Ltd. Kankakee, IL 60901, USA.
  • CSL Behring GmbH, Walcherstraße 1A/Stiege 1, 1020 Vienna, Austria.

Abstract

People living with sickle cell disease (SCD) face intermittent acute pain episodes due to vaso-occlusion primarily treated palliatively with opioids. Hemolysis of sickle erythrocytes promotes release of heme, which activates inflammatory cell adhesion proteins on endothelial cells and circulating cells, promoting vaso-occlusion. In this study, plasma-derived hemopexin inhibited heme-mediated cellular externalization of P-selectin and von Willebrand factor, and expression of IL-8, VCAM-1, and heme oxygenase-1 in cultured endothelial cells in a dose-responsive manner. In the Townes SCD mouse model, intravenous injection of free hemoglobin induced vascular stasis (vaso-occlusion) in nearly 40% of subcutaneous blood vessels visualized in a dorsal skin-fold chamber. Hemopexin administered intravenously prevented or relieved stasis in a dose-dependent manner. Hemopexin showed parallel activity in relieving vascular stasis induced by hypoxia-reoxygenation. Repeated IV administration of hemopexin was well tolerated in rats and non-human primates with no adverse findings that could be attributed to human hemopexin. Hemopexin had a half-life in wild-type mice, rats, and non-human primates of 80-102 h, whereas a reduced half-life of hemopexin in Townes SCD mice was observed due to ongoing hemolysis. These data have led to a Phase 1 clinical trial of hemopexin in adults with SCD, which is currently ongoing.

MeSH

Anemia, Sickle Cell, Plasma, Therapeutics, Endothelial Cells, Heme Oxygenase-1, P-Selectin, Hemoglobins, Hemopexin

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