DeCure for Hemolytic anemia due to erythrocyte adenosine deaminase overproduction
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for hemolytic anemia due to erythrocyte adenosine deaminase overproduction — 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 erythrocyte adenosine deaminase overproduction 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 erythrocyte adenosine deaminase overproduction 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.
What the evidence adds up to
A 40-fold increase in red cell adenosine deaminase activity was found in a patient with hereditary hemolytic anaemia, and the purified enzyme was structurally normal by multiple criteria including molecular weight, specific activity, Michaelis constant, thermal stability, and tryptic peptide mapping. The increase was therefore attributed to overproduction of a normal enzyme. In a separate case of primary acquired sideroblastic anaemia, erythrocyte ADA activity was 17 times the normal mean, with normal leukocyte ADA and a twofold elevation in plasma ADA; Western blotting showed increased ADA protein, but Southern blotting found no gene amplification, and dot blot analysis of reticulocyte mRNA showed no increase in ADA mRNA compared with reticulocyte-rich controls. The authors considered the mechanism similar to that in the hereditary form.
In the hereditary condition, ADA activity in younger red cells was twice that in older cells, and the rate of ADA synthesis in erythroid colony cells cultured from the patient's bone marrow was 11-fold greater than normal, indicating increased synthesis in erythroid precursors despite increased degradation in peripheral blood. A 2016 study identified a novel missense mutation in GATA1 (c.920G>A, p.R307H) in an 18-year-old Japanese male with a 30-fold elevation in ADA activity (39.7 IU/gHb, normal mean approximately 1.3 IU/gHb). The same mutation was found in a previously reported case, and both patients shared clinical features including low birth weight, hypospadias, splenomegaly, and slightly decreased platelet counts, suggesting classification as X-linked anaemia with neutropenia and/or platelet abnormality (XLANP). A 2020 study of a large family with autosomal dominant inheritance used a polymorphic TAAA repeat upstream of the ADA gene and found that all 11 affected individuals carried an allele with 12 repeats, while none of the 8 unaffected individuals did, supporting a cis-acting mutation near the ADA gene as the cause of overexpression.
A 2010 assay using dried blood spots and reversed-phase HPLC measured ADA activity in a Diamond Blackfan anaemia patient at 150 nmol/mg/h, compared with 41 nmol/mg/h in controls, and noted that heterozygotes for a c.704G>A mutation had only slightly decreased activity (35 nmol/mg/h). The disease is described as a rare genetic haematologic condition with mild chronic haemolytic anaemia, elevated reticulocyte count, splenomegaly, and mild hyperbilirubinemia, with no other tissues affected. What remains missing is a clear understanding of how the GATA1 mutation or the cis-acting regulatory change leads to the specific erythroid overexpression of ADA, and whether targeting ADA activity directly would alter the haemolytic course. No clinical trial has tested any intervention in these patients, and the small number of identified families makes patient stratification and trial design difficult.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Hemoglobin · 1980 · 19 citations
Purification and Properties of Adenosine Deaminase in Normal and Hereditary Hemolytic Anemia with Increased red Cell Activity
AbstractRed cell adenosine deaminase from normal subjects and from a patient with hereditary hemolytic anemia with a 40-fold increase in activity were purified using antibody affinity chromatography. The purified enzymes were completely homogeneous on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. There were no differences in the molecular weight, specific activity, polyacrylamide gel electrophoresis, Michaelis constant for adenosine, inhibition constant for guanylurea, utilization of 2-deoxyadenosine, thermal stability, optimum pH, immunological reactivity, amino acid composition and tryptic peptide mapping. These results strongly suggest that increased red cell adenosine deaminase activity is caused by an overproduction of a structurally normal enzyme.
American Journal of Hematology · 1988 · 8 citations
Elevated erythrocyte adenosine deaminase activity in a patient with primary acquired sideroblastic anemia
AbstractWe report a case of primary acquired sideroblastic anemia (PASA) associated with elevated erythrocyte adenosine deaminase (ADA) activity. The patient was an 85-year-old Japanese male. Analysis of the peripheral blood revealed pancytopenia, and the bone marrow findings showed marked ringed sideroblasts and chromosomal deletion (46XY, 11q-). The erythrocyte ADA activity was 17 times higher than that of normal control, the leukocyte ADA activity was within the normal range, and the plasma ADA activity was 2 times higher than the normal mean. The adenine nucleotides in the patient's erythrocytes were within normal range. According to starch gel electrophoresis, ADA isozyme of the patient was ADA 1. Western blotting showed an increased amount of ADA protein in the patient's erythrocytes. Southern blotting revealed no gene amplification or large structural change. Dot blot analysis of the reticulocyte mRNA showed no increase in the amount of ADA mRNA in the patient's reticulocytes compared with those of reticulocyte-rich controls. We considered that the mechanism of elevated ADA activity in this acquired defect was similar to that found in hereditary hemolytic anemia associated with ADA overproduction.
British Journal of Haematology · 1982 · 8 citations
Overproduction of structurally normal enzyme in man: hereditary haemolytic anaemia with increased red cell adenosine deaminase activity
AbstractThe mechanism of red cell adenosine deaminase (ADA) accumulation in a case of hereditary haemolytic anaemia due to increased red cell ADA activity was investigated. ADA activity of the younger cells was twice that of the older cells. Rate of ADA synthesis in erythroid colony cells cultured from the patient's bone marrow cells was 11-fold greater than that from the normal. The accumulation of ADA in the patient seems to be due to the increased synthesis in precursors of red cells in spite of the increased degradation in peripheral blood.
Determination of Adenosine Deaminase Activity in Dried Blood Spots by a Nonradiochemical Assay Using Reversed-Phase High-Performance Liquid Chromatography
AbstractAdenosine deaminase (ADA) deficiency is a rare metabolic disease causing severe combined immunodeficiency (SCID). An assay to determine ADA activity in dried blood spots was developed using reversed-phase HPLC. The assay was linear with reaction times up to at least 4 hours, and protein concentrations up to at least 2.2 mg/ml. The intra-assay CV and the inter-assay CV for the complete assay was 3.5 and 8.4%, respectively. The ADA activity in a control blood spot, stored at 4 degrees C, remained stable for at least one year. Only a slightly decreased ADA activity (35 +/- 13 nmol/mg/h, n = 4) was observed in heterozygotes for a c.704G > A mutation in the ADA gene when compared to that observed in controls (41 +/- 13 nmol/mg/h, n = 108). In addition, increased ADA activity as found in a rare form of congenital anemia can be assessed, as observed in a bloodspot from a patient diagnosed with Diamond Blackfan anemia (ADA activity 150 nmol/mg/h).
The Novel Missense Mutation of GATA1 Caused Red Cell Adenosine Deaminase Overproduction Associated with Congenital Hemolytic Anemia
AbstractAbstract Red cell adenosine deaminase (ADA) overproduction (OMIM 102730) is a rare form of congenital hemolytic anemia. To date, only four independent families have been reported. Recently, we examined the red cell enzyme activities of an 18-year-old male Japanese patient with congenital hemolytic anemia, and diagnosed a new case of ADA overproduction. His ADA activity was measured as 39.7 IU/gHb, representing an over 30-fold elevation of the normal mean value. The patient's mother also showed a high red cell ADA, 7.40 IU/gHb, and the father had normal ADA activity. To elucidate the molecular basis of the elevated ADA activity, we performed a target-captured sequencing focusing on the 67 congenital-anemia related genes. The results showed that there was no structural mutation of ADA gene, and that the proband had a novel missense mutation of GATA1, c.920G>A, p.R307H. The proband was hemizygous, and the mother was heterozygous for the mutation. Subsequently, we examined a previously reported case of ADA overproduction, and identified the identical missense mutation of GATA1. These two cases had clinical similarities, such as low birth weight with hypospadias, splenomegaly, and slightly decreased platelet counts, suggesting that these cases could be categorized as X-linked anemia with or without neutropenia and/or platelet abnormality (XLANP, OMIM#300835). The previous case showed a rare blood type, Lu(a-b-) and a low beta/alpha globin synthetic ratio, whereas the present case depicted abnormal red cell morphology, such as stomatocytosis and target cells. Taken together, the missense mutation of GATA1 might cause the aberrant expression of erythroid-genes, inducing a short life-span of red cells. Disclosures No relevant conflicts of interest to declare.
Hereditary overexpression of adenosine deaminase in erythrocytes: evidence for a cis-acting mutation.
AbstractOverexpression of adenosine deaminase (ADA) in red blood cells is inherited as an autosomal dominant trait and causes hemolytic anemia. The increased ADA activity in erythrocytes is due to an increase in steady-state levels of ADA mRNA of normal sequence. Increased ADA mRNA may be due to a cis-acting mutation which results in increased transcription or a loss of down-regulation during erythroid differentiation. Alternatively, it is possible that the mutation is in a trans-acting factor which interacts with normal ADA transcriptional elements to cause overexpression in red blood cells. To discriminate between a cis-acting and a trans-acting mutation, the authors took advantage of a highly polymorphic TAAA repeat located at the tail end of an Alu repeat approximately 1.1 kb upstream of the ADA gene. Using PCR to amplify this region, the authors identified five different alleles in 19 members of the family. All 11 affected individuals had an ADA allele with 12 TAAA repeats, whereas none of the 8 normal individuals did. The authors conclude that this disorder results from a cis-acting mutation in the vicinity of the ADA gene. 24 refs., 3 figs.
Hemolytic anemia due to erythrocyte adenosine deaminase overproduction
AbstractOpe n Pe e r Re v ie w on Qe ios Ope n Pe e r Re v ie w on Qe ios Hemolytic anemia due to erythrocyte adenosine deaminase overproduction INSERM Source INSERM.(1999).Orphanet: an online rare disease and orphan drug data base.Hemolytic anemia due to erythrocyte adenosine deaminase overproduction.ORPHA:99138Hemolytic anemia due to erythrocyte adenosine deaminase overproduction is a rare, genetic, hematologic disease characterized by mild, chronic hemolytic anemia (due to highly elevated adenosine deaminase activity in red blood cells resulting in their premature destruction), elevated reticulocyte count, splenomegaly and mild hyperbilirubinemia.Other cells and tissues are not affected.
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.
