DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for hyper-IgM syndrome type 3 — 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 moduleHyper-IgM syndrome type 3 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 hyper-igm syndrome type 3 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
CD40 molecule (CD40) — CD40 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7P3I · 2.29 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Hyper-IgM syndrome type 3 is a primary immunodeficiency. The hallmark of hyper-IgM syndromes is an inability to switch from one immunoglobulin isotype to another. Patients typically present with recurrent bacterial infections such as otitis media and pneumonia, along with opportunistic infections, recurrent neutropenia, lymphoid hyperplasia, and autoimmune manifestations. Serum immunoglobulin abnormalities include low or absent IgG, IgA, and IgE, with normal or elevated IgM and IgD. The condition can be inherited in an X-linked or autosomal recessive fashion. In one reported case of X-linked hyper-IgM syndrome, a 19-year-old male patient developed progressive multifocal leukoencephalopathy; his CD40 ligand expression on T cells was markedly reduced, and despite combined antiviral treatment, he died after six weeks.
Two patients with intrinsic B-cell class-switch defects, a subclass of hyper-IgM syndromes, were treated with rituximab for lymphoproliferation and autoimmunity. After starting rituximab, autoimmune phenomena and generalised lymphadenopathy disappeared and remained well controlled during an observation period of three to four years, with no adverse effects reported. Quality of life increased in both patients. No other drug treatments for hyper-IgM syndrome type 3 are described in these abstracts.
Diagnosis of hyper-IgM syndrome is frequently delayed by months to years, increasing morbidity. One case was diagnosed after seven months and multiple hospitalisations for multisystem pathologies. What remains missing is prospective data on rituximab in larger cohorts of hyper-IgM syndrome patients, standardised treatment protocols, and any evidence from controlled trials. No drug has been tested specifically for hyper-IgM syndrome type 3 in a randomised or adequately powered study.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
JAMA Dermatology · 2020 · 64 citations · open access
Use of Epidermal Growth Factor Receptor Inhibitor Erlotinib to Treat Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by <i>TRPV3</i> Mutations
AbstractImportance: Olmsted syndrome is a genodermatosis characterized by painful and mutilating palmoplantar keratoderma (PPK) that progresses from infancy onward and lacks an effective treatment. It is most often caused by mutations in the transient receptor potential vanilloid 3 (TRPV3) gene. In animal models and keratinocyte cell lines, TRPV3 signaling leads to epidermal growth factor receptor (EGFR) transactivation. Objective: To examine the possibility of blocking EGFR transactivation with the inhibitor erlotinib hydrochloride to treat PPK in patients with Olmsted syndrome due to TRPV3 mutations. Design, Setting, and Participants: In this case series, 3 patients from 2 unrelated families who had TRPV3-mutation-associated PPK were treated with erlotinib from May 5, 2018, through May 13, 2019. Main Outcomes and Measures: Clinical follow-up included evaluation of PPK progression, pain and interventions for pain, as well as erlotinib dose adjustment based on treatment effect, plasma levels, and tolerance. Results: The 3 patients (2 brothers aged 15 and 17 years and a 13-year-old girl) had severe palmoplantar hyperkeratosis, intolerable pain with erythromelalgia, severe growth delay, anorexia, and insomnia, which had been progressing since infancy despite numerous therapies. Two patients were confined to wheelchairs owing to intense pain and joint restrictions because of hyperkeratosis. All patients experienced depression and did not engage in social activities. Within 3 months of initiating therapy with erlotinib, hyperkeratosis and pain disappeared. All patients were able to touch the ground with their feet, wear shoes, and walk. Anorexia and insomnia remitted and paralleled improved growth. In addition, the patients resumed social activities. These improvements were sustained across 12 months of treatment and follow-up. The doses of erlotinib used were lower than those used in oncology, and only mild to moderate adverse effects were noted. Conclusions and Relevance: The findings of this study report improvement of PPK in patients with Olmsted syndrome caused by TRPV3 mutations when treated with erlotinib. Targeting EGFR transactivation with erlotinib therapy may result in clinical remission in an orphan disease that lacks an effective intervention.
Current Opinion in Pediatrics · 2014 · 45 citations
Hyper-IgE syndromes
AbstractPURPOSE OF REVIEW: The hyper-IgE syndromes have been recognized as a group of primary immunodeficiencies characterized by eczema, recurrent skin and lung infections, and elevated serum IgE. Recently, mutations in phosphoglucomutase 3 (encoding PGM3, which is involved in the protein glycosylation pathway) have been identified in autosomal recessive forms of hyper-IgE syndromes. RECENT FINDINGS: Autosomal recessive, hypomorphic PGM3 mutations cause a multisystem disorder, characterized by both a congenital glycosylation disease and a hyper-IgE syndrome. The reported mutations in PGM3 led to an impaired biosynthesis of UDP-GlcNAc and impaired tri-antennary and tetra-antennary N-glycan structures. Laboratory results in patients showed eosinophilia, a T-cell proliferation defect, and a reversed CD4/CD8 ratio. The impaired glycosylation in PGM3-mutant patients will not only affect proteins involved in the immune system, and thus causes a multisystem phenotype. SUMMARY: The identification of hyper-IgE syndromes-associated mutations in PGM3 provides the basis for future studies on the pathophysiology and the molecular mechanisms of eczema, IgE dysregulation, and increased susceptibility to infections.
New England Journal of Medicine · 1994 · 41 citations · open access
Prenatal Diagnosis of X-Linked Hyper-IgM Syndrome
AbstractThe inability to initiate switching from one immunoglobulin isotype to another is the hallmark of the hyper-IgM immunodeficiency syndrome1. Patients with this primary immune disorder, originally termed “dysgammaglobulinemia type 1,”2 usually present with recurrent bacterial infections, including otitis media and pneumonia. Additional clinical features include opportunistic infections, recurrent neutropenia, lymphoid hyperplasia, and autoimmune manifestations. Abnormalities of serum immunoglobulins include low levels or an absence of IgG, IgA, and IgE and normal or, more frequently, elevated levels of IgM and IgD. The hyper-IgM syndrome can be inherited in an X-linked or autosomal recessive fashion. The candidate gene for this disease . . .
Advances in Clinical and Experimental Medicine · 2021 · 24 citations · open access
The effectiveness of methotrexate and low-dose steroid therapy in the treatment of idiopathic granulomatous mastitis
AbstractBACKGROUND: Idiopathic granulomatous mastitis (IGM) is a rare, chronic, benign, inflammatory breast disease of unknown cause. Patients usually present with a single breast mass, hyperemia, discharge, skin disorders, and fever. Radiological and clinical findings can mimic carcinoma and infection. OBJECTIVES: To examine the treatment of IGM with methotrexate (MTX) + low-dose steroid, and present the results and follow-up data from our center. MATERIAL AND METHODS: Sixty-two patients, diagnosed with IGM in our center between January 2009 and December 2017 were included in this study. Patients diagnosed with granulomatous mastitis histopathologically underwent testing with anamnesis, physical examination and imaging methods to exclude other diseases that cause granulomatous reactions. Patients with a history of malignancy, chronic infectious diseases such as hepatitis B and pregnant women were excluded from this study. Data collected from 62 patients were reviewed retrospectively for this study. RESULTS: The mean patient age was 36.58 ±5.83 years (range: 28-54 years). Lesions were present in the right breast in 30 (48.38%) patients, the left breast in 26 (41.94%) patients and both breasts in 6 (9.68%) patients. Methotrexate was administered orally at a dose of 15 mg/week and methylprednisolone at a dose of 8 mg/day. The mean clinical and radiological remission periods of these patients were 10.14 ±1.21 months (range: 3-14 months). All patients attended regular follow-up appointments. The recovery rate of patients during follow-up was determined to be 93.71%. CONCLUSION: Methotrexate + low-dose steroid therapy is successful in the treatment of IGM. Prospective, large case series and/or multi-center studies are needed to develop an IGM treatment algorithm.
X-linked Hyper-IgM Syndrome Associated With a Rapid Course of Multifocal Leukoencephalopathy
AbstractOBJECTIVE: To report an exceptional association between X-linked hyper-IgM syndrome and progressive multifocal leukoencephalopathy. DESIGN: Clinical, immunological, and histological analysis. Patient A 19-year-old male patient with X-linked hyper-IgM syndrome developed typical signs and symptoms of progressive multifocal leukoencephalopathy. RESULTS: The serum level of IgA was decreased; the serum level of IgM was slightly increased; and the serum level of IgG was normal as a result of monthly infusions of immunoglobulin. The expression of CD40 ligand on T cells was markedly reduced in the patient. Magnetic resonance imaging indicated confluent lesions involving the majority of the right hemisphere with a mass effect. The patient died after 6 weeks despite combined antiviral treatment. CONCLUSION: Progressive multifocal leukoencephalopathy may follow a rapid course in patients with X-linked hyper-IgM syndrome because of global defects of cellular and B cell responses.
British Journal of Haematology · 2009 · 12 citations
Successful treatment of autoimmune and lymphoproliferative complications of patients with intrinsic B‐cell immunodeficiencies with Rituximab
AbstractThe heterogeneous group of primary immunodeficiencies requires personalized diagnosis and therapy to acheive an optimal outcome for each patient. This was exemplified by two patients with intrinsic B-cell class-switch defects (subclass of Hyper-IgM syndromes), where lymphoproliferation and autoimmunity determined the clinical course for many years due to lack of exact diagnosis. Based on genetics or a novel functional diagnostic approach, a definite individual diagnosis was established for each patient and they started Rituximab therapy. Autoimmune phenomena and generalized lymphadenopathy disappeared and remained well controlled during the observation period (3-4 years) without adverse effects. Quality of life increased remarkably in both patients.
AbstractPrimary immunodeficiency syndromes encompass a wide variety of inborn and acquired cellular and signaling defects. They are predominantly diagnosed during childhood but can present later into young adulthood depending on the severity, impact, and access to healthcare. Early clues to diagnosis include atypical and severe or recurrent presentations to common pathogens, vaccine failure, and immune lab abnormalities. Despite seemingly obvious characteristics, diagnosis is frequently delayed by months to years at a cost of greatly increased morbidity. Here we present a case of a challenging hyper IgM syndrome diagnosed after seven months and multiple hospitalizations for unique multisystem pathologies.
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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