DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for X-linked sideroblastic anemia 1 — screening already-approved drugs against its 4-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleX-linked sideroblastic anemia 1 maps to a 4-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 x-linked sideroblastic anemia 1 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
5'-aminolevulinate synthase 2 (ALAS2) — ALAS2 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 plpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6HRH · 2.3 Å · ligand PYRIDOXAL-5'-PHOSPHATE (PLP). Experimental structure, not a prediction.
What the evidence adds up to
X-linked sideroblastic anaemia (XLSA) is caused by germline mutations in ALAS2, the gene encoding erythroid-specific 5-aminolevulinate synthase. Hemizygous males typically present with a hypochromic microcytic anaemia that is generally mild to moderate, resulting from defective haem synthesis and ineffective erythropoiesis. XLSA is a classic iron-loading anaemia; most patients respond to pyridoxine, but managing iron overload is also important. Two-thirds of patients with ALAS2 mutations can have their anaemia alleviated with simple, non-transfusion therapy. Iron overload in some patients is worsened by red cell transfusion. Increased iron absorption is thought to be driven by suppression of hepcidin via growth/differentiation factor 15, mediated by ineffective erythropoiesis.
A 2013 report describes a large four-generation pedigree with a new ALAS2 mutation (c.622G>T, p.Val208Phe) that appears to cause male-lethal XLSA. The propositus was an adult heterozygous female with a mild congenital macrocytic anaemia (Hb 10.4 g/dL, MCV 107 fL), 38% ring sideroblasts, normal erythrocyte protoporphyrin (1.6 µmoles/L RBC), and elevated transferrin saturation (90%). She required transfusions only twice during pregnancy. Her daughter and mother carried the same mutation but lacked skewed X-chromosome inactivation and had normal blood counts. No affected males were identified in the pedigree; there were 22 females to 7 males, and 18 miscarriages occurred among mutation-carrying females. The ratio of males to females over four generations was close to 1:1 when miscarriages were counted, suggesting prenatal male lethality. The authors note that in female XLSA patients, a history of excess miscarriage should prompt consideration of a male-lethal form.
Autosomal recessive sideroblastic anaemia due to SLC25A38 mutations presents in infancy as a severe microcytic anaemia that soon becomes transfusion-dependent. Conservative management involves regular red cell transfusion and iron chelation; allogeneic stem cell transplantation is the only curative option. The most common acquired sideroblastic anaemia is refractory anaemia with ring sideroblasts (RARS), a myelodysplastic syndrome driven by somatic mutations in SF3B1 in more than 90% of cases. These mutations cause misrecognition of 3' splice sites, leading to truncated gene products and decreased expression. RARS generally follows an indolent course, but anaemia tends to worsen over time, and most patients eventually become transfusion-dependent. Inhibitors of transforming growth factor-β superfamily molecules have shown promise in animal models and in RARS patients for targeting ineffective erythropoiesis.
What remains missing is a systematic understanding of how many XLSA patients carry ALAS2 mutations that are not detected because the condition is under-recognised. No large prospective trial has tested pyridoxine response stratified by mutation type, and the natural history of iron overload in XLSA without transfusion is poorly quantified. For the male-lethal variant, no prenatal or neonatal screening strategy exists, and the mechanism linking the specific ALAS2 mutation to male lethality in utero is not established. For acquired RARS, the durability and safety of TGF-β superfamily inhibitors in unselected patients is not yet known.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Hematology · 2015 · 44 citations · open access
Diagnosis and treatment of sideroblastic anemias: from defective heme synthesis to abnormal RNA splicing
AbstractThe sideroblastic anemias are a heterogeneous group of inherited and acquired disorders characterized by the presence of ring sideroblasts in the bone marrow. X-linked sideroblastic anemia (XLSA) is caused by germline mutations in ALAS2. Hemizygous males have a hypochromic microcytic anemia, which is generally mild to moderate and is caused by defective heme synthesis and ineffective erythropoiesis. XLSA is a typical iron-loading anemia; although most patients are responsive to pyridoxine, treatment of iron overload is also important in the management of these patients. Autosomal recessive sideroblastic anemia attributable to mutations in SLC25A38, a member of the mitochondrial carrier family, is a severe disease: patients present in infancy with microcytic anemia, which soon becomes transfusion dependent. Conservative therapy includes regular red cell transfusion and iron chelation, whereas allogenic stem cell transplantation represents the only curative treatment. Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome characterized mainly by anemia attributable to ineffective erythropoiesis. The clinical course of RARS is generally indolent, but there is a tendency to worsening of anemia over time, so that most patients become transfusion dependent in the long run. More than 90% of these patients carry somatic mutations in SF3B1, a gene encoding a core component of the RNA splicing machinery. These mutations cause misrecognition of 3' splice sites in downstream genes, resulting in truncated gene products and/or decreased expression attributable to nonsense-mediated RNA decay; this explains the multifactorial pathogenesis of RARS. Variants of RARS include refractory cytopenia with multilineage dysplasia and ring sideroblasts, and RARS associated with marked thrombocytosis; these variants involve additional genetic lesions. Inhibitors of molecules of the transforming growth factor-β superfamily have been shown recently to target ineffective erythropoiesis and ameliorate anemia both in animal models of myelodysplastic syndrome and in RARS patients.
Indian Journal of Pathology and Microbiology · 2009 · 3 citations · open access
Congenital sideroblastic anemia: A report of two cases
AbstractSideroblastic anemia, comprising of acquired and congenital forms, is a heterogeneous group of disorders characterized by the presence of ring sideroblasts in the bone marrow. Congenital sideroblastic anemia is a rare condition which is mostly X-linked, caused by mutations of delta-aminolevulinic acid synthase 2. We describe two cases of congenital sideroblastic anemia, one of them indicating an autosomal recessive inheritance, with their clinico-hematological profile. It is important to recognize this entity early in life as a significant percentage of cases respond to pyridoxine thus avoiding any long-term complications.
A New ALAS2 Mutation Inducing a Male Lethal X-Linked Sideroblastic Anemia
AbstractAbstract X-linked Sideroblastic Anemia (XLSA, MIM# 300751) is due to mutations in the erythroid-specific form of 5-aminolevulinate synthase (ALAS2) gene. Main features of this condition are microcytic anemia, iron deposits in the mitochondria of erythroid precursors (ring sideroblasts) and an X linked pattern of inheritance. However, up to one third of described cases have been reported in females mainly due to a highly skewed X-chromosome inactivation (Ducamp, Kannengiesser et al. 2011). We report for the first time in a large four generations pedigree a new mutation in ALAS2 gene inducing a Male Lethal X-linked Syndrome ascertained through an adult heterozygous female with a mild form of congenital sideroblastic anemia (CSA). The propositus of this non consanguineous family (Fig 1; individual III;9) was a female from European ancestry. She exhibited a unexplained congenital, non regenerative, macrocytic (MCV 107fL, moderate anemia (Hb 10.4 g/dL), (first assessment at 6 years old). RBC transfusions were required only twice during pregnancy. The diagnosis of CSA was made at 23 years old when the bone marrow aspiration performed, showed 38% of ring sideroblasts. Erythrocyte protoporphyrin concentration was measured in the female proband carrying an ALAS2 mutation. The protoporphyrin concentration was within the normal range of values: 1.6 µmoles/L of red blood cells (less than 1.9 µmoles/L of red blood cells), as previously observed in XLSA cases. The level of serum ferritin was 224ng/ml (N:11-306) and transferrin saturation was 90%. A heterozygote ALAS2 deleterious missense mutation c.622G>T,p.Val208Phe affecting a conserved amino acid was found. A constitutive skewed X-chromosome inactivation was demonstrated as previously reported in affected females with XLSA. However erythroid bone marrow precursor did not exhibited different pattern repartition in term of apoptosis or dyserythropoisesis. Her daughter and her mother exhibited the same mutation but did not have skewed X-chromosome inactivation and were unaffected with a normal blood count. A close inspection of the pedigree confirms a large female predominance (22 females/ 7 males) over four generations (/F/M ratio 3.1). No affected male were identified in the pedigree. Moreover a high level of miscarriage was found only in female carrying the ALAS2 mutation, as shown in the pedigree (Fig. 1). Adding the number of miscarriage (18 over the four generations) to the number of males alive the ratio of M/F over 4 generation is close of 1: 1.04 (24/23). These data highly suggest an X-linked dominant disorder with pre natal male lethality. Our pedigree confirms the non redundant role of the erythroid-specific form of delta-aminolevulinate synthase in foetal hematopoïesis; Moreover our propositus case showed that in case of X-linked Sideroblastic Anemia (XLSA) affected female, a research of excess of miscarriage in the pedigree should be considered and should evocate a male lethal XLSA. This should have an impact in term of genetic counselling. Disclosures: No relevant conflicts of interest to declare.
AbstractABSTRACT: X-linked sideroblastic anemia (XLSA) in female carriers of 5-aminolevulinic acid synthase 2 mutations is not uncommon. We describe unique features and genotype/phenotype correlations in females with XLSA and evaluate the contributions of X-chromosome skewing and clonal hematopoiesis, emphasizing the importance of distinguishing it from myelodysplastic syndromes with ring sideroblasts.
Cambridge University Press eBooks · 2010 · 0 citations
Hereditary sideroblastic anemias
AbstractX-linked sideroblastic anemias (XLSA) are characterized by impaired mitochondrial iron metabolism, “ringed” sideroblasts and increased erythropoiesis. In some cases, these disorders cause parenchymal iron overload similar to that of hemochromatosis. Increased iron absorption is upregulated by relative or absolute suppression of hepcidin expression presumably mediated by ineffective erythropoiesis through growth/differentiation factor 15 (GDF15). Iron overload in some patients is exacerbated by erythrocyte transfusion. Mutations in the ALAS2 gene that encodes erythroid-specific 5-aminolevulinate synthase (ALA synthase) account for most cases (OMIM #300751), although rare mutations in other genes on the X chromosome or elsewhere also cause sideroblastic anemia phenotypes and variable degrees of iron loading. Anemia in two-thirds of patients with ALAS2 mutations can be alleviated with simple, non-transfusion therapy. Early recognition and treatment of iron accumulation prevents irreversible organ damage. Informal experience suggests that XLSA may be more common than is generally recognized.
AbstractThe sideroblastic anemias are a heterogeneous group of inherited and acquired disorders characterized by anemia of varying severity and the presence of ringed sideroblasts in the bone marrow.1 These latter are immature red cells with iron-loaded mitochondria visualized by Prussian blue staining as a perinuclear ring of blue granules. The most common of the inherited forms is X-linked sideroblastic anemia (XLSA, OMIM 301300), which is caused by mutations in the erythroid-specific ALA synthase gene (ALAS2). The most common acquired sideroblastic anemia is a myelodysplastic syndrome (MDS) defined as refractory anemia with ringed sideroblasts (RARS).2
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.
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