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

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

doi:10.3390/jcm11030630

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

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 MartinRoslyn Davis, Svetlana Didichenko, Alexander Schaub, Nathan Brinkman, Eva Herzog, Adrian Zürcher, Gregory M. Vercellotti, Gregory J. Kato, Gerald Höbarth

Medicine - Hematology, Oncology, Transplant

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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.

Original language	English (US)
Article number	630
Journal	Journal of Clinical Medicine
Volume	11
Issue number	3
DOIs	https://doi.org/10.3390/jcm11030630
State	Published - Feb 1 2022

Bibliographical note

Funding Information:
Moloegthyo:dTo.Glo.g,yJ.:DT..BG.,.,V J..BD..-BV..,, VJ..AB..,-VT..R, J..,AJ..B, .T,.MR..,MJ.B.,.M, M.P..M, K., .MM..,PR., .KD..M, S.,.DR..,DA.,.SS..;Din.,vAe.sSti.;g iantvioens:tigVa.Bti.o-Vn.:, JV.A.B..,-VJ.B., .J,.AD..,S J..,BL.,. VD.,.SM., .LE..V, .H, M.L..E, .K, H.P..,LC., .KC..P, .J,.NC..C, F.,. AJ.N.,.P, .FZ.A., .A, P.W.Z..,, MA..WM..,, MN..MB.;., wNr.iBti.;n wg–riotriniggi–noarligdirnaaftl pdrreapfta prarteipoanr:aTt.iGon.,:JT.D.G.B.,. ,J.VD.B.B.-.V, V., .TB.R.-V., .M, T.J..R, .G, M.J.K.J..,, GG..JH.K.;.,w Gr.iHtin.;gw–rreitviinegw–r&eveidewiti n&g:edT.iGtin.,gJ.:DT..BG..,,VJ..DB..-BV..,, JV.A.B.,.-TV.R., .J,.AJ.B.,.,TD.R.S.,. ,J.LB..V, D., M.S..,E L.,.VH..,L M.,.KE..,P .H, C.L.C., .K, J.P.N., .C, F.C.A.,. ,J.PN.Z.,. ,FA.A.W., .P, .MZ..,J .A, M.W.M., M., M.J..,P M., K.M.M., .M, R.P.D., .K, S.M.D..,, AR..DS..,, NS..DB..,, AE..HS..,, NA..BZ..,, EG.H.M.,. VA..,ZG.,. JG.K.M., G.V.H., G.; .vJ.iKsu.,a Gliz.Hat.i;o vnis: uTa.Gli.z,aVti.Bon.-:VT.,.GM..,M V..;Bs.u-Vp.e,rMvi.sMio.n; s:uTp.Ger.,vJi.sDio.Bn.:, T.G., J.D.B., E.H., A.Z., G.M.V., G.H. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by CSL Behring.

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

Heme
Hemoglobin
Hemopexin
Sickle cell anaemia
Vaso-occlusive crisis

PubMed: MeSH publication types

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/jcm11030630

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Gentinetta, T., Belcher, J. D., Brügger-Verdon, V., Adam, J., Ruthsatz, T., Bain, J., Schu, D., Ventrici, L., Edler, M., Lioe, H., Patel, K., Chen, C., Nguyen, J., Abdulla, F., Zhang, P., Wassmer, A., Jain, M., Mischnik, M., Pelzing, M., ... Höbarth, G. (2022). Plasma-Derived Hemopexin as a Candidate Therapeutic Agent for Acute Vaso-Occlusion in Sickle Cell Disease: Preclinical Evidence. Journal of Clinical Medicine, 11(3), Article 630. https://doi.org/10.3390/jcm11030630

Gentinetta, T, Belcher, JD, Brügger-Verdon, V, Adam, J, Ruthsatz, T, Bain, J, Schu, D, Ventrici, L, Edler, M, Lioe, H, Patel, K, Chen, C , Nguyen, J , Abdulla, F, Zhang, P, Wassmer, A, Jain, M, Mischnik, M, Pelzing, M, Martin, K, Davis, R, Didichenko, S, Schaub, A, Brinkman, N, Herzog, E, Zürcher, A, Vercellotti, GM, Kato, GJ & Höbarth, G 2022, 'Plasma-Derived Hemopexin as a Candidate Therapeutic Agent for Acute Vaso-Occlusion in Sickle Cell Disease: Preclinical Evidence', Journal of Clinical Medicine, vol. 11, no. 3, 630. https://doi.org/10.3390/jcm11030630

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

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.",

keywords = "Heme, Hemoglobin, Hemopexin, Sickle cell anaemia, Vaso-occlusive crisis",

author = "Thomas Gentinetta and Belcher, {John D.} and Val{\'e}rie Br{\"u}gger-Verdon and Jacqueline Adam and Tanja Ruthsatz and Joseph Bain and Daniel Schu and Lisa Ventrici and Monika Edler and Hadi Lioe and Kalpeshkumar Patel and Chunsheng Chen and Julia Nguyen and Fuad Abdulla and Ping Zhang and Andreas Wassmer and Meena Jain and Marcel Mischnik and Matthias Pelzing and Kirstee Martin and Roslyn Davis and Svetlana Didichenko and Alexander Schaub and Nathan Brinkman and Eva Herzog and Adrian Z{\"u}rcher and Vercellotti, {Gregory M.} and Kato, {Gregory J.} and Gerald H{\"o}barth",

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year = "2022",

month = feb,

day = "1",

doi = "10.3390/jcm11030630",

language = "English (US)",

volume = "11",

journal = "Journal of Clinical Medicine",

issn = "2077-0383",

number = "3",

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TY - JOUR

T1 - Plasma-Derived Hemopexin as a Candidate Therapeutic Agent for Acute Vaso-Occlusion in Sickle Cell Disease

T2 - Preclinical Evidence

AU - Gentinetta, Thomas

AU - Belcher, John D.

AU - Brügger-Verdon, Valérie

AU - Adam, Jacqueline

AU - Ruthsatz, Tanja

AU - Bain, Joseph

AU - Schu, Daniel

AU - Ventrici, Lisa

AU - Edler, Monika

AU - Lioe, Hadi

AU - Patel, Kalpeshkumar

AU - Chen, Chunsheng

AU - Nguyen, Julia

AU - Abdulla, Fuad

AU - Zhang, Ping

AU - Wassmer, Andreas

AU - Jain, Meena

AU - Mischnik, Marcel

AU - Pelzing, Matthias

AU - Martin, Kirstee

AU - Davis, Roslyn

AU - Didichenko, Svetlana

AU - Schaub, Alexander

AU - Brinkman, Nathan

AU - Herzog, Eva

AU - Zürcher, Adrian

AU - Vercellotti, Gregory M.

AU - Kato, Gregory J.

AU - Höbarth, Gerald

N1 - Funding Information: Moloegthyo:dTo.Glo.g,yJ.:DT..BG.,.,V J..BD..-BV..,, VJ..AB..,-VT..R, J..,AJ..B, .T,.MR..,MJ.B.,.M, M.P..M, K., .MM..,PR., .KD..M, S.,.DR..,DA.,.SS..;Din.,vAe.sSti.;g iantvioens:tigVa.Bti.o-Vn.:, JV.A.B..,-VJ.B., .J,.AD..,S J..,BL.,. VD.,.SM., .LE..V, .H, M.L..E, .K, H.P..,LC., .KC..P, .J,.NC..C, F.,. AJ.N.,.P, .FZ.A., .A, P.W.Z..,, MA..WM..,, MN..MB.;., wNr.iBti.;n wg–riotriniggi–noarligdirnaaftl pdrreapfta prarteipoanr:aTt.iGon.,:JT.D.G.B.,. ,J.VD.B.B.-.V, V., .TB.R.-V., .M, T.J..R, .G, M.J.K.J..,, GG..JH.K.;.,w Gr.iHtin.;gw–rreitviinegw–r&eveidewiti n&g:edT.iGtin.,gJ.:DT..BG..,,VJ..DB..-BV..,, JV.A.B.,.-TV.R., .J,.AJ.B.,.,TD.R.S.,. ,J.LB..V, D., M.S..,E L.,.VH..,L M.,.KE..,P .H, C.L.C., .K, J.P.N., .C, F.C.A.,. ,J.PN.Z.,. ,FA.A.W., .P, .MZ..,J .A, M.W.M., M., M.J..,P M., K.M.M., .M, R.P.D., .K, S.M.D..,, AR..DS..,, NS..DB..,, AE..HS..,, NA..BZ..,, EG.H.M.,. VA..,ZG.,. JG.K.M., G.V.H., G.; .vJ.iKsu.,a Gliz.Hat.i;o vnis: uTa.Gli.z,aVti.Bon.-:VT.,.GM..,M V..;Bs.u-Vp.e,rMvi.sMio.n; s:uTp.Ger.,vJi.sDio.Bn.:, T.G., J.D.B., E.H., A.Z., G.M.V., G.H. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by CSL Behring. Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2022/2/1

Y1 - 2022/2/1

N2 - 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.

AB - 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.

KW - Heme

KW - Hemoglobin

KW - Hemopexin

KW - Sickle cell anaemia

KW - Vaso-occlusive crisis

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UR - http://www.scopus.com/inward/citedby.url?scp=85123379399&partnerID=8YFLogxK

U2 - 10.3390/jcm11030630

DO - 10.3390/jcm11030630

M3 - Article

C2 - 35160081

AN - SCOPUS:85123379399

SN - 2077-0383

VL - 11

JO - Journal of Clinical Medicine

JF - Journal of Clinical Medicine

IS - 3

M1 - 630

ER -

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

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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