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Treatment strategies for glucose-6-phosphate dehydrogenase deficiency: past and future perspectives.

ABSTRACT: Glucose-6-phosphate dehydrogenase (G6PD) maintains redox balance in a variety of cell types and is essential for erythrocyte resistance to oxidative stress. G6PD deficiency, caused by mutations in the G6PD gene, is present in ~400 million people worldwide, and can cause acute hemolytic anemia. Currently, there are no therapeutics for G6PD deficiency. We discuss the role of G6PD in hemolytic and nonhemolytic disorders, treatment strategies attempted over the years, and potential reasons for their failure. We also discuss potential pharmacological pathways, including glutathione (GSH) metabolism, compensatory NADPH production routes, transcriptional upregulation of the G6PD gene, highlighting potential drug targets. The needs and opportunities described here may motivate the development of a therapeutic for hematological and other chronic diseases associated with G6PD deficiency.

SUBMITTER: Garcia AA

PROVIDER: S-EPMC8448981 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Treatment strategies for glucose-6-phosphate dehydrogenase deficiency: past and future perspectives.

Garcia Adriana A AA Koperniku Ana A Ferreira Julio C B JCB Mochly-Rosen Daria D

Trends in pharmacological sciences 20210810 10

Glucose-6-phosphate dehydrogenase (G6PD) maintains redox balance in a variety of cell types and is essential for erythrocyte resistance to oxidative stress. G6PD deficiency, caused by mutations in the G6PD gene, is present in ~400 million people worldwide, and can cause acute hemolytic anemia. Currently, there are no therapeutics for G6PD deficiency. We discuss the role of G6PD in hemolytic and nonhemolytic disorders, treatment strategies attempted over the years, and potential reasons for their ...[more]

PMID: 34389161

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Project description:BACKGROUNDGlucose-6-phosphate dehydrogenase (G6PD) deficiency decreases the ability of red blood cells (RBCs) to withstand oxidative stress. Refrigerated storage of RBCs induces oxidative stress. We hypothesized that G6PD-deficient donor RBCs would have inferior storage quality for transfusion as compared with G6PD-normal RBCs.METHODSMale volunteers were screened for G6PD deficiency; 27 control and 10 G6PD-deficient volunteers each donated 1 RBC unit. After 42 days of refrigerated storage, autologous 51-chromium 24-hour posttransfusion RBC recovery (PTR) studies were performed. Metabolomics analyses of these RBC units were also performed.RESULTSThe mean 24-hour PTR for G6PD-deficient subjects was 78.5% ± 8.4% (mean ± SD), which was significantly lower than that for G6PD-normal RBCs (85.3% ± 3.2%; P = 0.0009). None of the G6PD-normal volunteers (0/27) and 3 G6PD-deficient volunteers (3/10) had PTR results below 75%, a key FDA acceptability criterion for stored donor RBCs. As expected, fresh G6PD-deficient RBCs demonstrated defects in the oxidative phase of the pentose phosphate pathway. During refrigerated storage, G6PD-deficient RBCs demonstrated increased glycolysis, impaired glutathione homeostasis, and increased purine oxidation, as compared with G6PD-normal RBCs. In addition, there were significant correlations between PTR and specific metabolites in these pathways.CONCLUSIONBased on current FDA criteria, RBCs from G6PD-deficient donors would not meet the requirements for storage quality. Metabolomics assessment identified markers of PTR and G6PD deficiency (e.g., pyruvate/lactate ratios), along with potential compensatory pathways that could be leveraged to ameliorate the metabolic needs of G6PD-deficient RBCs.TRIAL REGISTRATIONClinicalTrials.gov NCT04081272.FUNDINGThe Harold Amos Medical Faculty Development Program, Robert Wood Johnson Foundation grant 71590, the National Blood Foundation, NIH grant UL1 TR000040, the Webb-Waring Early Career Award 2017 by the Boettcher Foundation, and National Heart, Lung, and Blood Institute grants R01HL14644 and R01HL148151.

Dataset Information

Treatment strategies for glucose-6-phosphate dehydrogenase deficiency: past and future perspectives.

Publications

Treatment strategies for glucose-6-phosphate dehydrogenase deficiency: past and future perspectives.

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