Mitapivat increases ATP and decreases oxidative stress and erythrocyte mitochondria retention in a SCD mouse model.

Apr 4, 2022

Contributor: Zenaide M N Quezado,Sayuri Kamimura,Meghann Smith,Xunde Wang,Michael R Heaven,Sirsendu Jana,Sebastian Vogel,Patricia Zerfas,Christian A Combs,Luis E F Almeida,Quan Li,Martha Quezado,Iren Horkayne-Szakaly,Penelope A Kosinski,Shaoxia Yu,Unnati Kapadnis,Charles Kung,Lenny Dang,Paul Wakim,William A Eaton,Abdu I Alayash,Swee Lay Thein

Polymerization of deoxygenated sickle hemoglobin (HbS) leads to erythrocyte sickling. Enhancing activity of the erythrocyte glycolytic pathway has anti-sickling potential as this reduces 2,3-diphosphoglycerate (2,3-DPG) and increases ATP, factors that decrease HbS polymerization and improve erythrocyte membrane integrity. These factors can be modulated by mitapivat, which activates erythrocyte pyruvate kinase (PKR) and improves sickling kinetics in SCD patients. We investigated mechanisms by which mitapivat may impact SCD by examining its effects in the Townes SCD mouse model. Control (HbAA) and sickle (HbSS) mice were treated with mitapivat or vehicle. Surprisingly, HbSS had higher PKR protein, higher ATP, and lower 2,3-DPG levels, compared to HbAA mice, in contrast with humans with SCD, in whom 2,3-DPG is elevated compared to healthy subjects. Despite our inability to investigate 2,3-DPG-mediated sickling and hemoglobin effects, mitapivat yielded potential benefits in HbSS mice. Mitapivat further increased ATP without significantly changing 2,3-DPG or hemoglobin levels, and decreased levels of leukocytosis, erythrocyte oxidative stress, and the percentage of erythrocytes that retained mitochondria in HbSS mice. These data suggest that, even though Townes HbSS mice have increased PKR activity, further activation of PKR with mitapivat yields potentially beneficial effects that are independent of changes in sickling or hemoglobin levels.
Published by Elsevier Inc.

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About The Expert

Zenaide M N Quezado

Department of Perioperative Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA; Sickle Cell Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: zquezado@nih.gov.

Sayuri Kamimura

Department of Perioperative Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.

Meghann Smith

Department of Perioperative Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.

Xunde Wang

Sickle Cell Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Michael R Heaven

Laboratory of Biochemistry and Vascular Biology, Center for Biologics Evaluation and Research, Food and Drug Administration (FDA), Silver Spring, MD 20993, USA.

Sirsendu Jana

Laboratory of Biochemistry and Vascular Biology, Center for Biologics Evaluation and Research, Food and Drug Administration (FDA), Silver Spring, MD 20993, USA.

Sebastian Vogel

Department of Perioperative Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.

Patricia Zerfas

Office of Research Services, Office of the Director, National Institutes of Health, Bethesda, MD 20892, USA.

Christian A Combs

Light Microscopy Core, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Luis E F Almeida

Department of Perioperative Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.

Quan Li

Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Martha Quezado

Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Iren Horkayne-Szakaly

Neuropathology and Ophthalmic Pathology, Joint Pathology Center, Defense Health Agency, Silver Spring, MD 20910, USA.

Penelope A Kosinski

Agios Pharmaceuticals Inc, Cambridge, MA 02139, USA.

Shaoxia Yu

Agios Pharmaceuticals Inc, Cambridge, MA 02139, USA.

Unnati Kapadnis

Agios Pharmaceuticals Inc, Cambridge, MA 02139, USA.

Charles Kung

Agios Pharmaceuticals Inc, Cambridge, MA 02139, USA.

Lenny Dang

Agios Pharmaceuticals Inc, Cambridge, MA 02139, USA.

Paul Wakim

Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Bethesda, MD 20892, USA.

William A Eaton

Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Abdu I Alayash

Laboratory of Biochemistry and Vascular Biology, Center for Biologics Evaluation and Research, Food and Drug Administration (FDA), Silver Spring, MD 20993, USA.

Swee Lay Thein

Sickle Cell Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.

References

PubMed