DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for hemoglobin E disease — screening already-approved drugs against its 7-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleHemoglobin E disease maps to a 7-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 hemoglobin e disease 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
hemoglobin subunit beta (HBB) — HBB 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 hemdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1DXT · 1.7 Å · ligand PROTOPORPHYRIN IX CONTAINING FE (HEM). Experimental structure, not a prediction.
What the evidence adds up to
The abstracts provided do not contain any study of eculizumab or any other drug in hemoglobin E disease. One abstract describes a randomised, double-blind, placebo-controlled trial of eculizumab in 87 transfusion-dependent adults with paroxysmal nocturnal hemoglobinuria (PNH). In that trial, haemoglobin stabilised in 21 of 43 eculizumab-treated patients (48.8%) versus none of 44 placebo-treated patients. Eculizumab-treated patients required a median of 0 units of red blood cell transfusions versus 10 units in the placebo group. Three patients developed serious meningococcal infections. The same abstract notes that patients must receive meningococcal vaccination at least two weeks before the first dose.
A separate abstract from 2014 summarises PNH as a rare clonal haematological disorder caused by an acquired PIG-A mutation, characterised by chronic intravascular haemolysis, marrow failure, and thrombophilia. It states that until recently treatment was symptomatic with transfusions, anticoagulation, and supplementation, and that the only potentially curative treatment is allogeneic stem cell transplantation, which carries high mortality. It reports that eculizumab has shown significant efficacy in controlling intravascular haemolysis, improving quality of life and survival in PNH.
The remaining abstracts are not relevant to hemoglobin E disease. One discusses anaemia improvement after percutaneous coronary intervention, another describes two different mutations causing Hb Malmö (a high-oxygen-affinity variant), and a third reports therapeutic erythrocytapheresis in two patients with high-altitude polycythaemia. An expert council abstract from 2023 discusses suboptimal response to C5 inhibitors in PNH and the use of pegcetacoplan, but again not in hemoglobin E disease.
There is no evidence in these abstracts for any drug treatment in hemoglobin E disease. What is missing is any clinical trial, any preclinical study, or any mechanistic rationale linking complement inhibition or any other agent to the pathophysiology of hemoglobin E disease. Without such data, no conclusion about efficacy or safety can be drawn.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
The Oncologist · 2008 · 137 citations · open access
FDA Report: Eculizumab (Soliris®) for the Treatment of Patients with Paroxysmal Nocturnal Hemoglobinuria
AbstractAbstract Learning Objectives After completing this course, the reader will be able to: Describe the mechanism of action of eculizumab in PNH.Discuss the efficacy findings upon which the approval of eculizumab was based.Manage the safety concerns surrounding the use of eculizumab for the treatment of patients with PNH.Discuss the efficacy and side effect profile of eculizumab. CME This article is available for continuing medical education credit at CME.TheOncologist.com On March 16, 2007, eculizumab (Soliris®; Alexion Pharmaceuticals, Inc. Cheshire, CT), a humanized monoclonal antibody that binds to the human C5 complement protein, received accelerated approval by the U.S. Food and Drug Administration for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. Eculizumab was studied in a randomized, double-blind, placebo-controlled clinical trial in 87 RBC transfusion–dependent adult PNH patients and in a supportive single-arm study in 96 patients. The eculizumab dose was 600 mg as a 35-minute i.v. infusion administered weekly for the first 4 weeks followed by 900 mg (week 5) then 900 mg every 14 days thereafter. Hemoglobin stabilized in 21 of 43 (48.8%) eculizumab-treated patients, compared with none of 44 placebo-treated patients. Eculizumab-treated patients required significantly fewer RBC transfusions than placebo-treated patients (median, 0 versus 10 units). There was also a significant reduction in the serum lactate dehydrogenase area under the curve with eculizumab compared with placebo treatment. Results of the phase II supportive study were similar to those of the phase III study. The safety database included 196 adult patients with PNH. Significant findings included the development of human anti-human antibody responses in three patients and serious meningococcal infections in three patients. Patients should undergo meningococcal vaccination at least 2 weeks prior to receiving the first eculizumab treatment and have revaccination according to current medical guidelines. Patients must be monitored and evaluated immediately for early signs of meningococcal infections and treated with antibiotics as indicated.
Eculizumab opens a new era of treatment for paroxysmal nocturnal hemoglobinuria
AbstractParoxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening and debilitating disorder of hematopoiesis. The only curative treatment is allogeneic stem cell transplantation. Other treatments are generally supportive in nature. Recently, eculizumab, as a targeted, disease-modifying treatment, was approved by the US FDA and the European Commission. Eculizumab is a humanized monoclonal antibody that inhibits complement factor C5. It is the first approved drug that specifically inhibits complement. This article presents the major aspects of PNH that are necessary to understand the mechanism of action of eculizumab. Experience from the pilot study and the Phase III pivotal program of eculizumab in PNH will be summarized and the impact of eculizumab on the future treatment of PNH will be discussed.
Improved anemia is associated with favorable long-term clinical outcomes in patients undergoing PCI
AbstractBACKGROUND: Anemia is associated with an increased risk of mortality in patients who underwent percutaneous coronary intervention (PCI) in the bare-metal stent era. However, there have been no data concerning the clinical importance of anemia improvement during the follow-up period after discharge from the hospital during the drug-eluting stent era. METHODS AND RESULTS: To assess anemia, the hemoglobin level was measured at the time of index PCI with drug-eluting stents and at the subsequent outpatient visit between 3 and 12 months later. Improvement of anemia was defined by the normalization of the hemoglobin level at the follow-up laboratory examination. We analyzed 4300 patients who were tested for initial and follow-up hemoglobin levels. We compared major adverse cardiac and cerebrovascular events (MACCE) between the normal group and the anemia group and between the improved anemia group and the sustained anemia group. The median follow-up period was 25.4 months. There was poorer clinical outcome in the anemia group than in the normal group in terms of MACCE (adjusted hazard ratio 1.479, 95% confidence interval 1.025-2.134, P=0.037). Furthermore, the sustained anemia group showed poorer MACCE than did the improved anemia group (hazard ratio 3.558, 95% confidence interval 2.285-5.539, P<0.0001). On the basis of the multivariate Cox hazard regression model and propensity-score matching, the overall findings were consistent between sustained and improved anemia groups. CONCLUSION: The follow-up of hemoglobin level is important, and improvement of anemia is associated with favorable long-term clinical outcomes.
American Journal of Hematology · 1996 · 5 citations
Two different mutations in codon 97 of the β-globin gene cause Hb Malmö in Sweden
AbstractAn abnormal hemoglobin with increased oxygen affinity, Hb Malmö [alpha 2 beta 297(FG4)His-->Gln], was found to cause erythrocytosis in two apparently unrelated Swedish families. Direct nucleotide sequencing of amplified DNA demonstrated a CAC-->CAA substitution in one family and a CAC-->CAG substitution in the other. Both mutations resulted in a His-->Gln substitution in codon 97. This finding prompted us to examine the possible point mutations underlying the different hemoglobin variants reported in the literature.
DOAJ (DOAJ: Directory of Open Access Journals) · 2014 · 1 citations · open access
Treatment of paroxysmal nocturnal hemoglobinuria
AbstractParoxysmal nocturnal hemoglobinuria (PNH) is a rare, life‑threatening clonal hematological disorder caused by an acquired mutation in the phosphatidylinositol glucan (PIG)-A gene. PNH is characterized by chronic intravascular hemolysis, marrow failure, thrombophilia and other severe clinical syndromes. Until recently, the treatment of PNH has been symptomatic with blood transfusions, anticoagulation and supplementation with folic acid or iron. The only potentially curative treatment is allogeneic stem cell transplantation, but this has severe complications with high mortality rates. A new targeted treatment strategy is the inhibition of the terminal complement cascade with anti‑C5 monoclonal antibody (eculizumab). Eculizumab has shown significant efficacy in controlling of intravascular hemolysis resulting in improving quality of life and survival.
Therapeutic Erythrocytapheresis is Effective in Treating 2 Patients with High-Altitude Erythrocythemia
AbstractBACKGROUND: Due to environmental hypoxia on the high-altitude local residents often exhibit a compensative increase in hemoglobin concentration to maintain the body's oxygen supply. In certain people, the number of red blood cells continues to grow, resulting in high altitude polycythemia (HAPC) which is characterized by headache, disorientation, sleeplessness, and bone discomfort. HAPC is often associated with multiple complications, of which lower extremity arteriosclerosis obliterans (LEASO) is rare. METHODS: Here we report two long-term Tibetan male patients living in plateau areas, who were diagnosed with HAPC complicated with LEASO. The diagnostic standards for HAPC are based on the Qinghai score, which is that the patient currently or once lived in high-altitude areas, and the results of conventional blood tests show that hemoglobin Hb > 21 g/dL in males and Hb > 19 g/dL in females. Due to severe complications caused by abnor-mally high hemoglobin levels, they underwent an individualized regimen of therapeutic erythrocytapheresis (TE). RESULTS: After one TE treatment, both hemoglobin and hematocrit decreased significantly in 2 patients (Hb decreased from 20 g/dL and 21 g/dL to 17.6 g/dL and 18 g/dL in the two patients), alleviating the further deterioration of the disease caused by abnormal erythrocyte elevation. CONCLUSIONS: TE can reduce the hemoglobin and hematocrit of HAPC patients in a timely and effective manner and play a clinical role in alleviating the disease progression of patients to a certain extent, especially for patients with complications. TE needs to be implemented in time.
Resolution of the Expert council “Unsolved problems of targeted therapy for paroxysmal nocturnal hemoglobinuria in Russia”
AbstractOn June 24, 2023, an Expert Council was held in St. Petersburg, during which leading experts in the field of hematology discussed current achievements and answered a number of unresolved issues of targeted therapy of paroxysmal nocturnal hemoglobinuria (APG) in order to further improve treatment results in Russia. During the Expert Council, the following aspects of targeted APG therapy were considered: • criteria for the suboptimal response of patients with APG to therapy with inhibitors of the 5th component of complement (C5); • efficacy and safety of the use of pegcetacoplan in APG in patients with insufficient efficacy of inhibitors of the C5 component of complement; • vaccination issues before starting therapy with complement inhibitors and the possibility of conducting treatment with pegcetacoplan at home.
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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