DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Bruton-type agammaglobulinemia — 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 moduleBruton-type agammaglobulinemia 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 bruton-type agammaglobulinemia 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
Bruton tyrosine kinase (BTK) — BTK 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 7h-pyrrolo[2,3-d]pyrimidin-4-yldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6VXQ · 1.4 Å · ligand N-{[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl]methyl}benzamide (RQS). Experimental structure, not a prediction.
What the evidence adds up to
Bruton-type agammaglobulinemia is an X-linked primary immunodeficiency caused by a mutation in the gene coding for Bruton’s tyrosine kinase (BTK). The disease frequency is estimated between 1:100,000 and 1:200,000. It is characterised by a sharp decrease in all classes of serum immunoglobulins and a very low number of circulating B lymphocytes. In a 2012 case series of four male patients, IgG ranged from undetectable to 197 mg/dL, IgM from undetectable to 98.7 mg/dL, IgA from undetectable to 10 mg/dL, and B cells from 0.02% to 2%. All four patients had infections before six months of age, including otitis, pansinusitis, septic arthritis, mastoiditis, and pneumonia; two had pleural effusion, and one had bronchiectasis and atelectasis. Maternal uncles had died at early ages in three of the four families.
A 2023 report of three clinical observations states that patients require lifelong replacement therapy with intravenous immunoglobulins, and that quality of life and prognosis depend on early detection and quality of medical care. No curative treatment is described in these clinical reports. A 1969 review notes that the discovery of agammaglobulinemia by Bruton in 1952 led to major insights into immunoglobulin metabolism and the immune response, but provides no specific therapeutic advance for the disease itself.
In 2014, a novel sequence variant in the BTK gene (c.240+109C>A) was identified in a patient with X-linked agammaglobulinemia. This alteration caused incorporation of 106 nucleotides of BTK intron 3 into the mRNA. In cultured peripheral blood mononuclear cells from that patient, a 25-mer antisense morpholino oligonucleotide was able to restore correctly spliced BTK mRNA. This is an in vitro finding in cells from a single patient; no in vivo treatment or clinical outcome is reported. Separately, a 2022 review discusses the use of Bruton tyrosine kinase inhibitors (ibrutinib, zanubrutinib, acalabrutinib, tirabrutinib) in Waldenström’s macroglobulinemia, a B-cell malignancy. These drugs inhibit BTK but are not proposed or tested as a treatment for Bruton-type agammaglobulinemia, where BTK is absent or dysfunctional rather than overactive.
What is still missing is any clinical trial of gene therapy, antisense oligonucleotide treatment, or other molecular correction in patients. The antisense approach has only been demonstrated in vitro. No data exist on whether restoring BTK splicing would improve immunoglobulin levels or reduce infection frequency in living patients. Funding for such a trial, a delivery method for the oligonucleotide to B-cell precursors in vivo, and patient stratification by specific BTK mutation type are all absent.
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 · 1969 · 97 citations
Disorders of Immunoglobulin Metabolism
AbstractSINCE the discovery of agammaglobulinemia in 1952 by Bruton, more than a score of diseases due to deficiencies of the immunologic system have been described. Clinical studies of patients with these disorders in conjunction with basic investigations in the laboratory have led to major insights into the sequence of biologic and chemical events involved in the immune response as well as the nature and metabolism of immunoglobulins. Two major forms of specific immune response have been considered: the delayed, or cellular, immune response; and the immediate, or antibody, response. The physiology of the cellular immune response and the genetic disorders . . .
Archivum Immunologiae et Therapiae Experimentalis · 2014 · 4 citations
In vitro Correction of a Novel Splicing Alteration in the BTK Gene by Using Antisense Morpholino Oligonucleotides
AbstractA novel sequence variant, c.240+109C>A, in the Bruton's tyrosine kinase (BTK) gene was identified in a patient with X-linked agammaglobulinemia. This alteration resulted in an incorporation of 106 nucleotides of BTK intron 3 into its mRNA. Administration of the 25-mer antisense morpholino oligonucleotide analog in the patient's cultured peripheral blood mononuclear cells was able to restore correctly spliced BTK mRNA, a potential treatment for X-linked agammaglobulinemia.
Journal of Personalized Medicine · 2022 · 2 citations · open access
The Use of Bruton Tyrosine Kinase Inhibitors in Waldenström’s Macroglobulinemia
AbstractWaldenström's macroglobulinemia (WM) remains an incurable malignancy. However, a number of treatment options exist for patients with WM, including alkylating agents, anti-CD20 monoclonal antibodies, and small molecule inhibitors such as proteasome inhibitors and Bruton tyrosine kinase inhibitors (BTKi). The focus of this review is to highlight the role of BTKi in the management of WM. The first BTKi to receive US Food and Drug Administration approval for WM was ibrutinib. Ibrutinib has been extensively studied in both treatment-naïve WM patients and in those with relapsed/refractory disease. The next BTKi approved for use was zanubrutinib, and prospective data for acalabrutinib and tirabrutinib have also recently been published. Efficacy data for BTKi will be discussed, as well as the differences in their adverse event profiles.
World Allergy Organization Journal · 2012 · 0 citations · open access
605 X-linked Agammaglobulinemia
AbstractBACKGROUND: The X-linked agammaglobulinemia is a primary immunodeficiency featured by hypogammaglobulinemia, recurrent infections and low levels of circulating B Lymphocytes, caused by a mutation of the tyrosine kinase of Bruton (Btk). The aim of this work is to present clinical and laboratory evidence of 4 patients with high suspect to bear a Bruton's agammaglobulinemia. METHODS: We review medical records of 4 patients bearing a humoral immunodeficiency probably Bruton's agammaglobulinemia. RESULTS: Patient 1: 20 years old with IgG of 197 mg/dL, IgM 14.6 mg/dL, IgA 10 mg/dL, IgE 0 UI/mL and B cells 0.02%. He has a brother with hypogammaglobulinemia, 2 maternal uncles died with history of recurrent infections. Patient 2: 13 years old, with IgG 33.3 mg/dL, IgM 6.07 mg/dL, IgA 6.07 mg/dL, IgE 0.5 UI/mL and B cells 0.03%. Six maternal uncles and 2 aunts have died at early age. Patient 3: 6 years old, IgG, IgM, IgA and IgE not detectable and B cells 0.4%. One brother died as newborn. Patient 4: 6 years old, with IgG 33 mg/dL, IgM 98.7 mg/dL, IgA 6.67 mg/dL and B cells 2%. The IgM maintained elevated until the age of 4 years old, afterwards was undetectable. He had 2 maternal uncles that had died at early age. All of our patients have presented infections before 6 months of age such as otitis, pansinusitis, septic arthritis, mastoiditis, pneumonia. Two of them with pleural efusion and patient 4 with bronchiectasis and atelectasis. CONCLUSIONS: Because of the clinical findings of our 4 patients, immunoglobulin levels, the low percentage of B cells, the early death of family members and all of them arer males, we consider that the molecular defect in our patients could be at Btk gene and the diagnosis most probable would be Bruton's agammaglobulinemia.
Familial Case of Hereditary Agammaglobulinemia Bruton Type
AbstractAim. To update the information about hereditary agammoglobulinemia, to describe a clinical case. Key Points. The frequency of hereditary agammaglobulinemia varies from 1:100,000 to 1:200,000. The cause of this disease is a gene mutation on the long arm of the X chromosome that codes for B-cell tyrosine kinase. The disease is characterized by a sharp decrease in all classes of serum immunoglobulins and the number of circulating B - lymphocytes. Hereditary agammaglobulinemia manifested by repeated bacterial infections during the first two years of life. Patients require lifelong replacement therapy with intravenous immunoglobulins. In this article we included 3 own clinical observations. Conclusion. The quality of life and prognosis of the patients with Bruton's disease depends on the early detection of the disease and the quality of medical care provided. Keywords: hereditary agammaglobulinemia, Bruton's disease, primary immune deficiencies, X-linked agammaglobulinemia
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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