1. The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a β-thalassemia mouse model
- Author
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Charles Kung, Carlo Brugnara, Maria Teresa Valenti, Sebastien Ronseaux, Iana Iatcenko, Tomas Ganz, Anne Janin, Penelope A. Kosinski, Rohini Narayanaswamy, Leonardo Salviati, Achille Iolascon, Francesca Carlomagno, Shaoxia Yu, Giorgia Federico, Enrica Federti, Lucia De Franceschi, Chun-Ling Jung, Alessandro Matte, Roberta Russo, Francesco Michelangelo Turrini, Elisabetta Beneduce, Christophe Leboeuf, Maria Andrea Desbats, Lenny Dang, Università degli studi di Verona = University of Verona (UNIVR), Agios Pharmaceuticals, CEINGE - Biotecnologie Avanzate, University of Naples Federico II = Università degli studi di Napoli Federico II, Università degli Studi di Padova = University of Padua (Unipd), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Università degli studi di Torino = University of Turin (UNITO), Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Université Paris Cité (UPCité), University of California [Los Angeles] (UCLA), University of California (UC), Harvard Medical School [Boston] (HMS), leboeuf, Christophe, Matte, A., Federti, E., Kung, C., Kosinski, P. A., Narayanaswamy, R., Russo, R., Federico, G., Carlomagno, F., Desbats, M. A., Salviati, L., Leboeuf, C., Valenti, M. T., Turrini, F., Janin, A., Yu, S., Beneduce, E., Ronseaux, S., Iatcenko, I., Dang, L., Ganz, T., Jung, C. -L., Iolascon, A., Brugnara, C., and De Franceschi, L.
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0301 basic medicine ,Ineffective erythropoiesis ,thalassemia ,Enzyme Activator ,Genetic disease ,Quinoline ,medicine.disease_cause ,Mouse models ,Transgenic ,Piperazines ,Mice ,0302 clinical medicine ,hemic and lymphatic diseases ,Glycolysis ,Chemistry ,General Medicine ,Hematology ,Erythroferrone ,Hemolysis ,030220 oncology & carcinogenesis ,Drug therapy ,Genetic diseases ,Animals ,Disease Models, Animal ,Enzyme Activators ,Female ,Mice, Transgenic ,Pyruvate Kinase ,Quinolines ,beta-Thalassemia ,Erythropoiesis ,HAMP ,medicine.drug ,Research Article ,medicine.medical_specialty ,Hemolysi ,[SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT] ,Mouse model ,03 medical and health sciences ,Internal medicine ,medicine ,Piperazine ,ineffective erythropoiesis ,[SDV.OT] Life Sciences [q-bio]/Other [q-bio.OT] ,Animal ,medicine.disease ,030104 developmental biology ,Endocrinology ,Erythropoietin ,Disease Models ,iron homeostasis ,Pyruvate kinase - Abstract
International audience; Anemia in β-thalassemia is related to ineffective erythropoiesis and reduced red cell survival. Excess free heme and accumulation of unpaired α-globin chains impose substantial oxidative stress on β-thalassemic erythroblasts and erythrocytes, impacting cell metabolism. We hypothesized that increased pyruvate kinase activity induced by mitapivat (AG-348) in the Hbb th3/+ mouse model for β-thalassemia would reduce chronic hemolysis and ineffective erythropoiesis through stimulation of red cell glycolytic metabolism. Oral mitapivat administration ameliorated ineffective erythropoiesis and anemia in Hbb th3/+ mice. Increased ATP, reduced reactive oxygen species production, and reduced markers of mitochondrial dysfunction associated with improved mitochondrial clearance suggested enhanced metabolism following mitapivat administration in β-thalassemia. The amelioration of responsiveness to erythropoietin resulted in reduced soluble erythroferrone, increased liver Hamp expression, and diminished liver iron overload. Mitapivat reduced duodenal Dmt1 expression potentially by activating the pyruvate kinase M2-HIF2α axis, representing a mechanism additional to Hamp in controlling iron absorption and preventing β-thalassemia-related liver iron overload. In ex vivo studies on erythroid precursors from patients with β-thalassemia, mitapivat enhanced erythropoiesis, promoted erythroid maturation, and decreased apoptosis. Overall, pyruvate kinase activation as a treatment modality for β-thalassemia in preclinical model systems had multiple beneficial effects in the erythropoietic compartment and beyond, providing a strong scientific basis for further clinical trials.
- Published
- 2021
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