DeCure for Hemolytic anemia due to glutathione reductase deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for hemolytic anemia due to glutathione reductase deficiency — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleHemolytic anemia due to glutathione reductase deficiency maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for hemolytic anemia due to glutathione reductase deficiency is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
glutathione-disulfide reductase (GSR) — GSR is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet faddrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2AAQ · 2.6 Å · ligand FLAVIN-ADENINE DINUCLEOTIDE (FAD). Experimental structure, not a prediction.
What the evidence adds up to
A 1970 study identified a 32-year-old man with a well compensated hemolytic disorder whose erythrocytes were completely devoid of glutathione synthetase activity. His parents and four children had half-normal enzyme levels and no other haematological abnormalities. Glutathione synthetase deficiency was described as an autosomal recessive trait that, in homozygotes, produces a mild haemolytic disorder. A 1978 paper distinguished two clinical syndromes: one with haemolytic anaemia and 5-oxoprolinuria, in which all cell types have grossly deficient enzyme activity and glutathione content; the other with isolated haemolysis, in which erythrocytes have decreased activity and glutathione content but nucleated cells maintain substantial levels of both. In the non-oxoprolinuric variant the enzyme is unstable in vitro and has shortened survival in intact erythrocytes.
A 1970 study on glucose-6-phosphate dehydrogenase deficiency found that in intact erythrocytes the inability to regenerate reduced glutathione was apparent regardless of red cell concentration, but in haemolysates the defect could only be demonstrated at haemoglobin concentrations below 2.0 g per 100 ml. The authors warned against extrapolating haemolysate results to intact cell metabolism. A 2009 report described three cases of haemolytic anaemia and pancytopenia with glutathione reductase deficiency. Riboflavin was given to raise enzyme activity because flavin adenine dinucleotide is the prosthetic group of glutathione reductase. Despite the return of glutathione reductase activity to normal values, the haemolytic anaemia and pancytopenia did not improve. The authors suggested these cases might represent a latent form of leukaemia.
No trial has tested a drug that corrects the underlying enzyme deficiency in glutathione synthetase deficiency. For glutathione reductase deficiency, riboflavin failed to improve clinical outcomes even when enzyme activity normalised. What is missing is a clear understanding of whether these disorders are primary enzyme defects or secondary phenomena, and whether any intervention can alter the haemolytic course. No randomised trial, no patient stratification by genetic subtype, and no funding for such work has been reported.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
New England Journal of Medicine · 1970 · 108 citations
Glutathione Synthetase Deficiency as a Cause of Hereditary Hemolytic Disease
AbstractTwo enzymes are required for de novo glutathione synthesis: glutamyl-cysteine synthetase and glutathione synthetase. In a 32-year-old man with a well compensated hemolytic disorder, the erythrocytes were devoid of glutathione synthetase activity, whereas erythrocytes from his parents and four children had levels that were half those of normal control erythrocytes. These heterozygotes had no other detectable hematologic abnormalities. Both the patient and his heterozygous relatives had normal levels of erythrocyte glutamyl-cysteine synthetase. Glutathione synthetase deficiency is an autosomally inherited trait that, in a homozygous subject, produces a mild hemolytic disorder.
Studies on Erythrocytes in Cases with Past History of Favism and Drug-Induced Acute Hemolytic Anemia
AbstractAbstract Studies have been carried out on erythrocytes of cases with past history of acute hemolysis due to Favism, sulpha drugs or PAS. No indication was found of abnormal osmotic or mechanical fragility, electrophoretic mobility of hemoglobin or its amino acid content. Similarly no abnormal glycolytic or catalase activities were detected. Glutathione (GSH) deficiency of erythrocytes was discovered in all cases studied. Similarly, glutathione (GSH) deficiency was a frequent finding among the relatives of affected cases. No such glutathione deficiency could be established in the cases of thalassemia major so far studied, though both patient-groups without any exception belong to the same ethnographic denomination (non-Ashkenazic). This investigation was aided by a grant from the Israel Research Council.
Journal of Clinical Investigation · 1978 · 51 citations · open access
Biochemical heterogeneity in glutathione synthetase deficiency.
AbstractTwo different clinical syndromes are associated with glutathione synthetase deficiency, one presenting with hemolytic anemia and 5-oxoprolinuria, the other with isolated hemolysis. We have differentiated these disorders on an enzymatic basis. In 5-oxoprolinuria, all cell types examined have grossly deficient enzyme activity and glutathione content. In contrast, in the nonoxoprolinuric variant, erythrocytes have decreased enzyme activity and glutathione content, whereas nucleated cells maintain substantial levels of both. The enzyme in this disorder is unstable in vitro and has shortened survival in intact erythrocytes. Nucleated cells appear able to maintain sufficient enzyme activity and concentrations of glutathione to suppress overproduction of 5-oxoproline.
Reduction of Oxidized Glutathione in Normal and Glucose-6-Phosphate Dehydrogenase Deficient Erythrocytes and Their Hemolysates
AbstractAbstract When assayed by the ability to reduce oxidized glutathione to reduced glutathione, glucose-6-phosphate dehydrogenase deficiency of either the Negro or Caucasian mutant variety could be demonstrated in hemolysates only with hemoglobin concentrations below 2.0 Gm. per 100 ml. In intact erythrocytes, the inability to regenerate reduced glutathione was apparent regardless of the concentration of red cells. The process of hemolysis, therefore, appeared to permit the demonstration of higher levels of activity in G-6-PD deficient human erythrocytes than was possible in intact cells. A markedly deficient capacity to regenerate endogenous reduced glutathione or to reduce exogenous oxidized glutathione, however, could be demonstrated with the hemolysate of erythrocytes from a patient with hereditary nonspherocytic hemolytic anemia associated with a deficiency of glucose-6-phosphate dehydrogenase activity. These studies have emphasized the hazards involved in extrapolating the results of studies performed with hemolysates to metabolic processes within intact erythrocytes.
Hemolytic Anemia and Pancytopenia in Glutathione Reductase Deficiency: Further Experience with Riboflavin
AbstractThree cases of hemolytic anemia and pancytopenia with glutathione reductase (GR) deficiency are described. Since flavin adenine dinucleotide is the prosthetic group of GR, riboflavin was administered in order to increase the enzyme activity. Despite the return of the GR activity to normal values, the hemolytic anemia and pancytopenia did not improve. It is conceivable that our cases might represent a latent form of leukemia.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
