DeCure for Severe combined immunodeficiency due to DNA-PKcs deficiency
DeCure's autonomous Immuno AI scientist is researching a drug-repurposing hypothesis for severe combined immunodeficiency due to DNA-PKcs deficiency — 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 moduleSevere combined immunodeficiency due to DNA-PKcs deficiency 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 severe combined immunodeficiency due to dna-pkcs deficiency 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
protein kinase, DNA-activated, catalytic subunit (PRKDC) — PRKDC 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 ~{s}drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7Z87 · 2.91 Å · ligand (~{S})-[2-chloranyl-4-fluoranyl-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol (1IX). Experimental structure, not a prediction.
What the evidence adds up to
Five boys with X-linked severe combined immunodeficiency received ex vivo gene therapy using a retroviral vector to insert the common gamma chain gene into their own CD34+ bone marrow cells. Within four months, transduced T cells and natural killer cells appeared in four of the five patients. T cell numbers, receptor repertoire, and in vitro proliferative responses to several antigens were nearly normal for up to two years. Thymopoiesis was documented by naive T cells and T-cell receptor excision circles. Transduced B cell frequency was low, but serum immunoglobulins and antibody production after immunisation were sufficient to avoid intravenous immunoglobulin. Established infections cleared and the patients could have a normal life. No adverse effects were reported.
A separate study identified a biallelic splice-site mutation in PRKCD, causing absence of protein kinase C delta, in a patient from a consanguineous family with recurrent infections and severe lupus-like autoimmunity. Immunophenotyping showed progressive decrease of CD19+ B cells, defective class switch with low numbers of IgM and IgG memory B cells, and increased CD21low B cells. Phosphorylation of myristoylated alanine-rich C kinase substrate was decreased, and mRNA levels of nuclear factor interleukin-6 and IL-6 were increased. This was described as a novel cause of common variable immunodeficiency-like B-cell deficiency with severe autoimmunity.
Swiss newborn screening for severe T and B cell deficiency using a combined TREC/KREC assay began in January 2019. The authors note that outcomes for SCID are greatly improved by early diagnosis and treatment with allogeneic haematopoietic stem cell transplantation or, in selected cases, gene therapy. The screening also reveals infants with non-SCID severe T and B cell disorders who are often diagnosed with substantial delay. Recommendations are given for diagnostic evaluations and precautionary measures against infection in children with abnormal screening results.
A pair of siblings with PNKP deficiency presented with microcephaly, eye abnormalities, and hypogammaglobulinemia. Whole-exome sequencing identified variants. Patient-derived fibroblasts showed defects in DNA repair in response to radiation-induced DNA breaks. Flow cytometry revealed reduced total B-cell and class-switched memory B-cell counts. B-cell receptor repertoire analysis demonstrated reduced frequencies of somatic hypermutations in these patients, whereas other PNKP-deficient patients without severe immunodeficiency had normal B-cell receptor repertoire patterns. The authors conclude that variant-induced DNA repair abnormalities may be associated with immunodeficiency. What remains missing is a unified trial design that can accommodate the genetic heterogeneity of SCID and related B-cell deficiencies, sufficient funding for long-term follow-up of gene therapy recipients, and patient stratification strategies that distinguish DNA repair defects from other molecular causes before treatment selection.
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 · 2002 · 1051 citations · open access
Sustained Correction of X-Linked Severe Combined Immunodeficiency by ex Vivo Gene Therapy
AbstractBACKGROUND: X-linked severe combined immunodeficiency due to a mutation in the gene encoding the common gamma (gamma(c)) chain is a lethal condition that can be cured by allogeneic stem-cell transplantation. We investigated whether infusion of autologous hematopoietic stem cells that had been transduced in vitro with the gamma(c) gene can restore the immune system in patients with severe combined immunodeficiency. METHODS: CD34+ bone marrow cells from five boys with X-linked severe combined immunodeficiency were transduced ex vivo with the use of a defective retroviral vector. Integration and expression of the gamma(c) transgene and development of lymphocyte subgroups and their functions were sequentially analyzed over a period of up to 2.5 years after gene transfer. RESULTS: No adverse effects resulted from the procedure. Transduced T cells and natural killer cells appeared in the blood of four of the five patients within four months. The numbers and phenotypes of T cells, the repertoire of T-cell receptors, and the in vitro proliferative responses of T cells to several antigens after immunization were nearly normal up to two years after treatment. Thymopoiesis was documented by the presence of naive T cells and T-cell antigen-receptor episomes and the development of a normal-sized thymus gland. The frequency of transduced B cells was low, but serum immunoglobulin levels and antibody production after immunization were sufficient to avoid the need for intravenous immunoglobulin. Correction of the immunodeficiency eradicated established infections and allowed patients to have a normal life. CONCLUSIONS: Ex vivo gene therapy with gamma(c) can safely correct the immune deficiency of patients with X-linked severe combined immunodeficiency.
B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C δ
AbstractPrimary B-cell disorders comprise a heterogeneous group of inherited immunodeficiencies, often associated with autoimmunity causing significant morbidity. The underlying genetic etiology remains elusive in the majority of patients. In this study, we investigated a patient from a consanguineous family suffering from recurrent infections and severe lupuslike autoimmunity. Immunophenotyping revealed progressive decrease of CD19(+) B cells, a defective class switch indicated by low numbers of IgM- and IgG-memory B cells, as well as increased numbers of CD21(low) B cells. Combined homozygosity mapping and exome sequencing identified a biallelic splice-site mutation in protein C kinase δ (PRKCD), causing the absence of the corresponding protein product. Consequently, phosphorylation of myristoylated alanine-rich C kinase substrate was decreased, and mRNA levels of nuclear factor interleukin (IL)-6 and IL-6 were increased. Our study uncovers human PRKCD deficiency as a novel cause of common variable immunodeficiency-like B-cell deficiency with severe autoimmunity.
Swiss Medical Weekly · 2020 · 35 citations · open access
Swiss newborn screening for severe T and B cell deficiency with a combined TREC/KREC assay – management recommendations
AbstractThe recent introduction of newborn screening for severe primary T and B cell deficiencies in Switzerland allows rapid identification of patients with severe combined immunodeficiency (SCID). Outcomes for SCID are greatly improved by early diagnosis and treatment with allogeneic haematopoietic stem cell transplantation or, in selected cases, gene therapy. National centralised newborn screening is performed in Switzerland since January 2019 using a combined T cell receptor excision circles (TREC) / κ-deleting recombination excision circles (KREC) assay, also revealing infants with non-SCID severe T and B cell disorders, who are often diagnosed with a substantial delay. Here, we outline the screening procedure currently performed in Switzerland and give recommendations for diagnostic evaluations and precautionary measures against infection in children with abnormal screening test results.
AbstractSevere combined immunodeficiency is one of the most common causes of primary immunodeficiencies in humans. Molecular biological techniques have allowed new, therapeutically useful treatments for these diseases to be introduced into clinical practice. This review will focus on the molecular basis and new treatments for X-linked severe combined immunodeficiency.
Journal of Allergy and Clinical Immunology Global · 2025 · 0 citations · open access
B-cell immunodeficiency associated with polynucleotide kinase 3′-phosphatase (PNKP) deficiency
AbstractBackground: DNA repair is crucial for maintaining genomic integrity and plays a significant role in the immune system. Defects in DNA repair pathways are often associated with immunodeficiency, including B-cell defects, which are consistent with the need for DNA repair during V(D)J recombination, class switching, and somatic hypermutation during B-cell maturation. Polynucleotide kinase 3'-phosphatase (PNKP) plays a significant role in DNA repair. PNKP deficiency is characterized by neurologic developmental abnormalities; however, immunodeficiency has not yet been reported. Objective: We focused on a pair of PNKP-deficient siblings who presented with microcephaly, eye abnormalities, and hypogammaglobulinemia. We aimed to analyze the effect of PNKP deficiency on B-cell development. Methods: Whole-exome sequencing was performed to identify the genetic cause of hypogammaglobulinemia. DNA repair efficiency was analyzed using patient-derived fibroblasts. The immune phenotype and B-cell receptor repertoire were analyzed using the patient's peripheral blood, alongside other patients with PNKP deficiency without severe immunodeficiency. Results: variants. Fibroblasts revealed defects in DNA repair in response to radiation-induced double/single-stranded DNA breaks. Flow cytometry revealed reduced total B-cell and class-switched memory B-cell counts. The B-cell receptor repertoire analysis demonstrated reduced frequencies of somatic hypermutations in these patients, whereas other patients with PNKP deficiency exhibited normal B-cell receptor repertoire patterns. Conclusion: variant-induced DNA repair abnormalities may be associated with immunodeficiency.
Severe combined immunodeficiency due to IKK2 deficiency
AbstractOpe n Pe e r Re v ie w on Qe ios Ope n Pe e r Re v ie w on Qe ios Severe combined immunodeficiency due to IKK2 deficiency INSERM Source INSERM.(1999).Orphanet: an online rare disease and orphan drug data base.Severe combined immunodeficiency due to IKK2 deficiency.ORPHA:397787 Severe combined immunodeficiency due to IKK2 deficiency is a rare, genetic form of primary immunodeficiency characterized by life-threatening bacterial, fungal and viral infections with the onset in infancy, and failure to thrive.T ypically, hypogammaglobulinemia or agammaglobulinemia and normal levels of T and B cells are present.
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.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
