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

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.
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, [...]