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

Trends Pharmacol Sci. 2021 Oct;42(10):829-844. doi: 10.1016/j.tips.2021.07.002. Epub 2021 Aug 10.

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.

Trial registration: ClinicalTrials.gov NCT02937363 NCT02124083 NCT03056495 NCT03894826 NCT03167437.

Keywords: G6PD deficiency; N-acetyl-cysteine; enzyme activators; therapeutic strategy; transcriptional regulators.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Glucosephosphate Dehydrogenase Deficiency* / genetics
  • Glutathione / metabolism
  • Humans
  • Mutation
  • Oxidation-Reduction
  • Oxidative Stress

Substances

  • Glutathione

Associated data

  • ClinicalTrials.gov/NCT02937363
  • ClinicalTrials.gov/NCT02124083
  • ClinicalTrials.gov/NCT03056495
  • ClinicalTrials.gov/NCT03894826
  • ClinicalTrials.gov/NCT03167437