DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Nijmegen breakage syndrome — screening already-approved drugs against its 19-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleNijmegen breakage syndrome maps to a 19-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 nijmegen breakage syndrome 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
MYCN proto-oncogene, bHLH transcription factor (MYCN) — MYCN 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 adpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5G1X · 1.72 Å · ligand ADENOSINE-5'-DIPHOSPHATE (ADP). Experimental structure, not a prediction.
What the evidence adds up to
Nijmegen breakage syndrome is an autosomal recessive DNA repair disorder caused by mutations in the NBN gene, which codes for the protein nibrin. Over 90% of patients are homozygous for a founder five-base-pair deletion (657del5), often called the “Slavic mutation.” The syndrome is characterised by microcephaly present at birth and progressive with age, dysmorphic facial features, mild growth retardation, mild-to-moderate intellectual disability, combined cellular and humoral immunodeficiency with recurrent sino-pulmonary infections, and a strong predisposition to malignancies, predominantly of lymphoid origin. More than 40% of patients develop haematopoietic malignancies by age 20. Chromosomal instability with rearrangements of peripheral T-lymphocytes involving chromosomes 7 and 14, and cellular sensitivity to ionising radiation in vitro, are diagnostic features. No specific therapy is available; haematopoietic stem cell transplantation may be an option for some patients. Prognosis is generally poor due to the high rate of malignancies.
In a series of 17 children with NBS and non-Hodgkin lymphoma (median age 9.5 years), nine had T-cell and eight had B-cell lymphoma. They received BFM or LMB type protocols with reduced cytostatic doses in the first courses. None complied with the timing of chemotherapy. Complete remission after induction was achieved in 8 of 9 T-NHL patients but only 3 of 8 B-NHL patients. All patients experienced grade 4 toxicities. Two died from complications. Six of 17 patients were alive. Those who received more than 80% of recommended drug doses all survived; treatment-related deaths occurred only in patients who received less than 80%. However, no differences in the type or number of responses or in grade 3 and 4 toxicities were observed between patients receiving less or more than 80% of drug doses. The authors concluded that treatment outcome is poor and might be improved by administering over 80% of drug doses.
A separate case report describes a 5-year-old with NBS and nodular sclerosing Hodgkin disease stage IVB treated with a COPP/ABV regimen at 75% of full doses. No major toxic or infectious complications occurred, and complete remission was achieved and lasted 20 months. The authors note that in DNA repair disorders the prognosis of Hodgkin disease is poor, and that better survival may require disease-specific regimens and individualised approaches. A 2025 literature review and clinical case report reiterates that increased sensitivity to ionising radiation is a separate risk factor: frequent X-ray examinations due to recurrent bacterial infections may contribute to the emergence or complicated course of malignant processes, particularly leukaemia and lymphoma.
A proteomic study in Nbn null mutant mice found that among approximately 8,000 resolved proteins, 209 were differentially expressed after 4 Gy irradiation in the absence of nibrin. Proteins involved in oxidative stress and cellular redox homeostasis were significantly altered, and null mutant fibroblasts showed increased production of reactive oxygen species after induction of DNA double-strand breaks. The authors suggest that the particularly high cancer risk in NBS may be attributable to a compound effect of a DNA repair defect and oxidative stress. What is still missing are prospective trials that establish safe and effective chemotherapy dosing for these patients, a better understanding of how to stratify patients by tumour type and genetic background, and funding to support the development of targeted therapies that address both the repair defect and the oxidative stress component.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
BioEssays · 1999 · 95 citations
Nijmegen breakage syndrome: consequences of defective DNA double strand break repair
AbstractThe autosomal recessive genetic disorder, Nijmegen Breakage Syndrome, is characterised by an excessively high risk for the development of lymphatic tumours and an extreme sensitivity towards ionising radiation. The most likely explanation for these characteristics, a deficiency in the repair of DNA lesions, has been greatly substantiated by the recent cloning of the gene mutated in Nijmegen Breakage Syndrome patients and the analysis of its protein product, nibrin. The direct involvement of this protein in the processing of DNA double strand breaks caused by ionising radiation and those also necessary for normal DNA metabolism can be correlated with many of the cellular and clinical aspects of the disease, including the cancer predisposition of patients and their heterozygous relatives.
Non‐Hodgkin lymphoma (NHL) in children with Nijmegen Breakage syndrome (NBS)
AbstractBACKGROUND: Due to small number of patients with Nijmegen Breakage Syndrome (NBS) and Non-Hodgkin lymphoma (NHL) experience in their treatment is limited. PROCEDURE: Since 1996, 17 patients with a median age of 9.5 years who had NBS, were treated for NHL. NHL type, stage, chemotherapy, dose modifications, chemotherapy delays, response to chemotherapy, toxicity, outcome and correlation of drug reduction with response to treatment and outcome were analyzed. RESULTS: Nine patients had TNHL, eight BNHL. TNHL patients received BFM and BNHL LMB type protocols. Doses of cytostatics were reduced in the first chemotherapy courses. Further modifications depended on severity of complications. None of the patients complied with timing of chemotherapy. Complete remissions after induction were achieved in 8 of 9 TNHL and 3 out 8 of BNHL patients. All patients experienced grade 4 toxicities. Two patients died from complications. Six of 17 patients are alive. All received more than 80% of recommended doses of chemotherapy. No differences in the type, number of responses or grade 3 and 4 toxicities between patients receiving less or more than 80% of drug doses were observed. Treatment related deaths concerned patients who received less than 80% of drug doses. CONCLUSIONS: Patients with NBS develop both T and B cell lymphomas. Treatment outcome is poor and might be improved by administering over 80% of drug doses. Although toxicity often depends upon drug doses, our patients experienced equal grade 3 and 4 toxicities whether they received more or less than 80% of the chemotherapeutic agents.
Pan African Medical Journal · 2020 · 25 citations · open access
Nijmegen breakage syndrome: case report and review of literature
AbstractNijmegen Breakage Syndrome (NBS) is a rare autosomalrecessive DNA repair disorder characterized by genomic instability andincreased risk of haematopoietic malignancies observed in morethan 40% of the patients by the time they are 20 years old. The underlying gene, NBS1, is located on human chromosome 8q21 and codes for a protein product termed nibrin, Nbs1 or p95. Over 90% of patients are homozygous for a founder mutation: a deletion of five base pairs which leads to a frame shift and protein truncation. Nibrin (NBN) plays an important role in the DNA damage response (DDR) and DNA repair. DDR is a crucial signalling pathway in apoptosis and senescence. Cardinal symptoms of Nijmegen breakage syndrome are characteristic: microcephaly, present at birth and progressive with age, dysmorphic facial features, mild growth retardation, mild-to-moderate intellectual disability, and, in females, hypergonadotropic hypogonadism. Combined cellular and humoral immunodeficiency with recurrent sino-pulmonary infections, a strong predisposition to develop malignancies (predominantly of lymphoid origin) and radiosensitivity are other integral manifestations of the syndrome. The diagnosis of NBS is initially based on clinical manifestations and is confirmed by genetic analysis. Prenatal molecular genetic diagnosis is possible if disease-causing mutations in both alleles of the NBN gene are known. No specific therapy is available for NBS; however, hematopoietic stem cell transplantation may be one option for some patients. Prognosis is generally poor due to the extremely high rate of malignancies. We present here a case of Nijmegen breakage syndrome associated with Hodgkin lymphomas and Combined variable immunodeficiency.
A Systematic Proteomic Study of Irradiated DNA Repair Deficient Nbn-Mice
AbstractBACKGROUND: The NBN gene codes for the protein nibrin, which is involved in the detection and repair of DNA double strand breaks (DSBs). The NBN gene is essential in mammals. METHODOLOGY/PRINCIPAL FINDINGS: We have used a conditional null mutant mouse model in a proteomics approach to identify proteins with modified expression levels after 4 Gy ionizing irradiation in the absence of nibrin in vivo. Altogether, amongst approximately 8,000 resolved proteins, 209 were differentially expressed in homozygous null mutant mice in comparison to control animals. One group of proteins significantly altered in null mutant mice were those involved in oxidative stress and cellular redox homeostasis (p<0.0001). In substantiation of this finding, analysis of Nbn null mutant fibroblasts indicated an increased production of reactive oxygen species following induction of DSBs. CONCLUSIONS/SIGNIFICANCE: In humans, biallelic hypomorphic mutations in NBN lead to Nijmegen breakage syndrome (NBS), an autosomal recessive genetic disease characterised by extreme radiosensitivity coupled with growth retardation, immunoinsufficiency and a very high risk of malignancy. This particularly high cancer risk in NBS may be attributable to the compound effect of a DSB repair defect and oxidative stress.
Journal of Pediatric Hematology/Oncology · 2008 · 13 citations
Successful Treatment of Hodgkin Lymphoma in Nijmegen Breakage Syndrome
AbstractNijmegen breakage syndrome (NBS) is a rare DNA repair disorder characterized by microcephaly, immunodeficiency, and predisposition to malignancy. We report on a 5-year-old patient with NBS who presented with nodular sclerosing type of Hodgkin disease stage IVB. Chemotherapy consisting of COPP/ABV regimen with reduction at 75% of full doses was employed. During this treatment, no major toxic or infectious complications were observed. Complete remission was achieved lasting now for 20 months. In DNA repair disorders, prognosis of Hodgkin disease is poor as opposed to excellent overall prognosis in general pediatric population. Better survival may be achieved both with adopted, disease-specific regimens, and individualized approach considering patient's clinical condition. Also, better recognition and treatment of infections during chemotherapy may reduce early deaths in patients with DNA repair disorders.
The Journal of V N Karazin Kharkiv National University series Medicine · 2025 · 0 citations · open access
Nijmegen breakage syndrome in pediatric practice (literature review and personal observation)
AbstractBackground. Nijmegen breakage syndrome is a rare autosomal recessive disease characterized by microcephaly, specific facial features, immunodeficiency, and an increased susceptibility to malignancies. Purpose – is to highlight the importance of the pathology of Nijmegen breakage syndrome in pediatric practice, to demonstrate oneʼs own experience in a clinical case. Materials and methods. An analysis and generalization of the results of scientific research for 1985–2025, selected on the basis of an information search in the scientometric databases Scopus, Web of Science, PubMed, MEDLINE, Google Scholar using the keywords «Nijmegen breakage syndrome», «immunodeficiency», «clinical features», «laboratory features», «genotype», «phenotype», was carried out. The majority of articles were represented by clinical studies and case presentations (73%). For the literature review, data were also obtained from sources containing literature reviews (27%). The most frequently cited sources in the article were from the years 2022–2024. Results and discussion. Nijmegen breakage syndrome is caused by mutations in the NBN gene, which encodes the protein nibrin, which is important for the repair of double-stranded DNA breaks. The most common mutation is a 5-base pair deletion (657del5), which leads to genomic instability and increased sensitivity to ionizing radiation. Parents of children with this syndrome are heterozygous carriers of the mutation, and the risk of having an affected child is 25% if both parents are carriers of the defective gene. Chromosomal instability with characteristic rearrangements of peripheral T-lymphocytes in the form of inversions and translocations involving chromosomes 7 and 14, sensitivity of cells to ionizing radiation in vitro — all these are characteristic features of this disease that have important diagnostic value. Detection of mutations in both alleles of the nibrin gene is the final study in making the diagnosis. Most patients with Nijmegen breakage syndrome are of Slavic origin, so this mutation began to be called the «Slavic mutation». Our work presents a clinical case of Nijmegen breakage syndrome in a patient with bacterial destruction of the lungs. Increased sensitivity to ionizing radiation is a separate risk factor for patients with Nijmegen breakage syndrome. Due to frequent bacterial infections, children in this group are often subjected to multiple X-ray examinations, which can contribute to the emergence of malignant processes or the complicated course of already existing malignant processes, in particular leukemia and lymphoma. Conclusions. Nijmegen breakage syndrome is a rare genetic disease that requires a multidisciplinary approach for its diagnosis and treatment. The relevance of further research is due to the need for a deeper understanding of the pathogenesis of Nijmegen breakage syndrome and the development of new strategies for the comprehensive treatment of this pathological condition in children.The clinical case presented in our work demonstrates the importance of a comprehensive analysis and a thorough approach for the timely diagnosis and treatment of a rare disease, which may be an «incidental finding» in the practice of doctors of various specialties.
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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