2. Academic Validation
  3. The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a β-thalassemia mouse model

The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a β-thalassemia mouse model

  • J Clin Invest. 2021 May 17;131(10):e144206. doi: 10.1172/JCI144206.
Alessandro Matte 1,  Enrica Federti 1,  Charles Kung 2,  Penelope A Kosinski 2,  Rohini Narayanaswamy 2,  Roberta Russo 3,  Giorgia Federico 3,  Francesca Carlomagno 3,  Maria Andrea Desbats 4,  Leonardo Salviati 4,  Christophe Leboeuf 5 6 7,  Maria Teresa Valenti 1,  Francesco Turrini 8,  Anne Janin 5 6 7,  Shaoxia Yu 2,  Elisabetta Beneduce 1,  Sebastien Ronseaux 2,  Iana Iatcenko 1,  Lenny Dang 2,  Tomas Ganz 9,  Chun-Ling Jung 9,  Achille Iolascon 3,  Carlo Brugnara 10,  Lucia De Franceschi 1
Affiliations

Affiliations

  • 1 Department of Medicine, University of Verona, and Azienda Ospedaliera Universitaria Verona, Policlinico GB Rossi, Verona, Italy.
  • 2 Agios Pharmaceuticals, Inc., Cambridge, Massachusetts, USA.
  • 3 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, and CEINGE Biotecnologie Avanzate, Naples, Italy.
  • 4 Clinical Genetics Unit, Department of Women and Children's Health, University of Padova, and Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy.
  • 5 Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.
  • 6 Université Paris 7 - Denis Diderot, Paris, France.
  • 7 AP-HP, Hôpital Saint-Louis, Paris, France.
  • 8 Department of Oncology, University of Torino, Torino, Italy.
  • 9 Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA.
  • 10 Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
PMID: 33822774 DOI: 10.1172/JCI144206
Abstract

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 Hbbth3/+ 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 Hbbth3/+ 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.

Keywords

Drug therapy; Genetic diseases; Hematology; Mouse models.

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