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

Authors :
Matte, Alessandro
Federti, Enrica
Kung, Charles
Kosinski, Penelope A.
Narayanaswamy, Rohini
Russo, Roberta
Federico, Giorgia
Carlomagno, Francesca
Desbats, Maria Andrea
Salviati, Leonardo
Leboeuf, Christophe
Valenti, Maria Teresa
Turrini, Francesco
Janin, Anne
Yu, Shaoxia
Beneduce, Elisabetta
Ronseaux, Sebastien
Iatcenko, Iana
Dang, Lenny
Ganz, Tomas
Jung, Chun-Ling
Iolascon, Achille
Brugnara, Carlo
De Franceschi, Lucia
Source :
Journal of Clinical Investigation. May 15, 2021, Vol. 131 Issue 10
Publication Year :
2021

Abstract

Anemia in [beta]-thalassemia is related to ineffective erythropoiesis and reduced red cell survival. Excess free heme and accumulation of unpaired [alpha]-globin chains impose substantial oxidative stress on [beta]-thalassemic erythroblasts and erythrocytes, impacting cell metabolism. We hypothesized that increased pyruvate kinase activity induced by mitapivat (AG-348) in the [Hbb.sup.th3/+] mouse model for [beta]-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.sup.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 [beta]-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-HIF2[alpha] axis, representing a mechanism additional to Hamp in controlling iron absorption and preventing [beta]-thalassemia-related liver iron overload. In ex vivo studies on erythroid precursors from patients with [beta]-thalassemia, mitapivat enhanced erythropoiesis, promoted erythroid maturation, and decreased apoptosis. Overall, pyruvate kinase activation as a treatment modality for [beta]-thalassemia in preclinical model systems had multiple beneficial effects in the erythropoietic compartment and beyond, providing a strong scientific basis for further clinical trials.<br />Introduction Ineffective erythropoiesis and reduced red cell survival are key determinants of the anemia and other comorbidities in [beta]-thalassemia (1-3). Reduced [beta]-chain production leads to a decoupling from heme production, [...]

Details

Language :
English
ISSN :
00219738
Volume :
131
Issue :
10
Database :
Gale General OneFile
Journal :
Journal of Clinical Investigation
Publication Type :
Academic Journal
Accession number :
edsgcl.677389332
Full Text :
https://doi.org/10.1172/JCI144206