DeCure for Severe combined immunodeficiency due to IKK2 deficiency
DeCure's autonomous Immuno AI scientist is researching a drug-repurposing hypothesis for severe combined immunodeficiency due to IKK2 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 IKK2 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 ikk2 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
inhibitor of nuclear factor kappa B kinase subunit beta (IKBKB) — IKBKB 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 ksadrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4KIK · 2.83 Å · ligand K-252A (KSA). Experimental structure, not a prediction.
What the evidence adds up to
Two girls from a consanguineous Turkish family, both homozygous for an IL-2–inducible T cell kinase (ITK) mutation (R335W), died after developing severe immune dysregulation and therapy-resistant EBV-positive B cell proliferation following EBV infection. The mutation caused near-undetectable ITK protein in transfected cells and was associated with absence of NKT cells and high eomesodermin in CD8+ cells. The authors proposed ITK deficiency as a novel immunodeficiency syndrome leading to fatal inadequate immune response to EBV.
A separate 2021 study identified IKKα deficiency as a cause of primary immunodeficiency with autoimmunity, based on a homozygous missense mutation in inhibitor of nuclear factor κB kinase alpha. Mice with this mutation showed severe reduction in medullary thymic epithelial cells, impaired thymocyte negative selection, restricted TCRVβ repertoire, expansion of potentially autoreactive T cell clones, decreased regulatory T cells, and infiltration of liver, pancreas, and lung by activated T cells with organ damage.
A novel homozygous missense mutation in IKBKB (Y395H) was found in a patient with combined immunodeficiency and immune dysregulation. Patient PBMCs and Ikbkb Y397H mouse cells lacked or showed decreased IKKβ protein, with normal IKKα and IKKγ expression. IKKβ degradation was accelerated, and NF-κB binding to DNA fell upon TNF-α or LPS stimulation. A structural model predicted loss of a hydrogen bond with D389, increasing protein instability. In two related Saudi families, four patients with a novel homozygous nonsense mutation in IKBKB (c.850C>T, p. Arg284*) had early onset severe infections, hypogammaglobulinaemia, low absolute lymphocyte count, and failure to respond to PHA mitogen stimulation. One patient underwent hematopoietic stem cell transplantation from a fully matched sibling with no conditioning; the other three died. All had delayed umbilical cord separation.
A systematic review of primary immunodeficiency in Korea identified 398 PID patients from 101 reports, including 11 with immunodeficiencies affecting cellular and humoral immunity and 40 with combined immunodeficiency with associated or syndromic features. From national insurance data, 1,162 outpatients and 306 inpatients were treated for PID in 2017, with total reimbursements of approximately $6.6 million. An infant with IL-7Rα deficient T-B+NK+ SCID who received only supportive treatment was described from a low-middle income country lacking resources for definitive therapy. What remains missing for IKK2 deficiency specifically is systematic prospective data on outcomes of HSCT with different conditioning regimens, larger patient cohorts to define genotype-phenotype correlations, and functional studies clarifying why some mutations cause protein instability while others lead to complete loss of expression.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Clinical Investigation · 2009 · 291 citations · open access
Girls homozygous for an IL-2–inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation
AbstractThe fatal immune dysregulation that sometimes follows EBV infection in boys has been linked to mutations in two X chromosome-encoded genes, SLAM-associated protein (SAP) and X-linked inhibitor of apoptosis (XIAP). In this study we describe 2 girls from a consanguineous Turkish family who died after developing severe immune dysregulation and therapy-resistant EBV-positive B cell proliferation following EBV infection. SNP array-based genome-wide linkage analysis revealed IL-2-inducible T cell kinase (ITK) as a candidate gene for this immunodeficiency syndrome. Both girls harbored a homozygous missense mutation that led to substitution of a highly conserved residue (R335W) in the SH2 domain of ITK. Characteristics of ITK deficiency in mouse models, such as absence of NKT cells and high levels of eomesodermin in CD8+ cells, were seen in either one or both of the girls. Two lines of evidence suggested that R335W caused instability of the ITK protein. First, in silico modeling of the mutant protein predicted destabilization of the SH2 domain. Additionally, Western blot analysis revealed that, unlike wild-type ITK, the R335W mutant was nearly undetectable when expressed in 293 T cells. Our results suggest that ITK deficiency causes what we believe to be a novel immunodeficiency syndrome that leads to a fatal inadequate immune response to EBV. Because ITK deficiency resembles EBV-associated lymphoproliferative disorders in boys, we suggest that this molecular cause should be considered during diagnosis and treatment.
Science Immunology · 2021 · 23 citations · open access
Combined immunodeficiency with autoimmunity caused by a homozygous missense mutation in inhibitor of nuclear factor 𝛋B kinase alpha (IKKα)
Abstractinfection. In addition, these mice demonstrate a severe reduction in medullary thymic epithelial cells, impaired thymocyte negative selection, a restricted TCRVβ repertoire, a selective expansion of potentially autoreactive T cell clones, a decreased frequency of regulatory T cells, and infiltration of liver, pancreas, and lung by activated T cells coinciding with organ damage. Hence, this study identifies IKKα deficiency as a previously undescribed cause of primary immunodeficiency with associated autoimmunity.
Frontiers in Immunology · 2021 · 18 citations · open access
A Novel Homozygous Mutation Destabilizes IKKβ and Leads to Human Combined Immunodeficiency
AbstractMutations in the IKBKB gene cause severe immunodeficiency, characterized clinically by persistent respiratory or gastrointestinal infections. Targeted gene panel sequencing revealed a novel homozygous missense mutation in the IKBKB gene of a patient with immune dysregulation and combined T and B cell functional defects. PBMCs from the patient, Ikbkb Y397H mice, and transfected cells were used to elucidate how the Y395H mutation triggers IKKβ deficiency and impairs immune function. Here, we found that cells from both the patient and Ikbkb Y397H mice lacked or showed decreased levels of IKKβ protein, along with impaired lymphocyte function. IKKα and IKKγ protein expression by human PBMCs harboring the Y395H mutation was normal, but degradation of IKKβ protein was accelerated. Binding of human NF-κB to DNA in patient PBMCs fell upon stimulation with TNF-α or LPS. Additionally, a structural model of Y395H revealed loss of the hydrogen bond with D389. These data suggest that IKBKB deficiency induces abnormal IKKβ protein degradation, leading to impaired NF-κB signaling and immune function. We postulate that the Y395H variant in the IKKβ protein lost the hydrogen bond with D389, thereby affecting interaction between Y395 and D389 and increasing protein instability.
Frontiers in Pediatrics · 2020 · 9 citations · open access
Multiple Family Members With Delayed Cord Separtion and Combined Immunodeficiency With Novel Mutation in IKBKB
AbstractBackground: Inhibitor of Kappa Kinase 2 (IKK2) deficiency is a recently described combined immunodeficiency. It undermines the NF-κB activation pathway. Methods: The clinical and immunological data of four patients diagnosed with combined immunodeficiency (CID) from two related Saudi families were collected. Autozygosity mapping of all available members and whole exome sequencing of the index case were performed to define the genetic etiology. Results: The patients had early onset (2-4months of age) severe infections caused by viruses, bacteria, mycobacteria and fungi. They all had hypogammaglobinemia and low absolute lymphocyte count. Their lymphocytes fail to respond to PHA mitogen stimulation. A novel homozygous nonsense mutation in IKBKB gene, c.850C>T (p. Arg284*) was identified in the index patient and segregated with the disease in the rest of the family. He underwent hematopoietic stem cell transplantation (HSCT) from a fully matched sibling with no conditioning. The other three patients succumbed to their disease. Interestingly, all patients had delayed umbilical cord separation. Conclusion: IKK2 deficiency causes combined immunodeficiency (CID) with high mortality. Immune reconstitution with HSCT should be considered as early as possible. Delayed umbilical cord separation in CID patients may be a clue to IKK2 deficiency.
Clinical and Experimental Pediatrics · 2020 · 6 citations · open access
Systematic review of literature and analysis of big data from the National Health Insurance System on primary immunodeficiencies in Korea
AbstractThere are very scant data on the epidemiology of primary immunodeficiency diseases (PIDs) in Korea. Here we attempted to estimate the PID epidemiology and disease burden in Korea. A systematic review was performed of studies retrieved from the PubMed, KoreaMed, and Google Scholar databases. Studies on PIDs published in Korean or English between January 2001 and November 2018 were analyzed. The number of PID patients and the healthcare costs were estimated from Health Insurance Review and Assessment Service (HIRA) Korea data for 2017. A total of 398 PID patients were identified from 101 reports. Immunodeficiencies affecting cellular and humoral immunity were reported in 11 patients, combined immunodeficiency with associated or syndromic features in 40, predominantly antibody deficiencies in 144, diseases of immune dysregulation in 58, congenital defects of phagocytes in 104, defects in the intrinsic and innate immunity in 1, auto-inflammatory disorders in 4, complement deficiencies in 36, and phenocopies of PID in none. From the HIRA reimbursement data, a total of 1,162 outpatients and 306 inpatients were treated for 8,166 and 6,149 days, respectively. In addition, reimbursement was requested for 8,200 outpatient and 1,090 inpatient cases and $1,924,000 and $4,715,000 were reimbursed in 2017, respectively. This study systematically reviewed published studies on PID and analyzed the national open data system of the HIRA to estimate the disease burden of PID, for the first time in Korea.
The Pediatric Infectious Disease Journal · 2014 · 1 citations
A Perspective on IL-7Rα Deficient T−B+NK+ Severe Combined Immunodeficiency
AbstractThe management of patients with IL-7Rα deficient, T-B+NK+ severe combined immunodeficiency (SCID) is a challenge in absence of adequate diagnostic and treatment modalities. An infant diagnosed as SCID at 6 months of age, who received only supportive treatment is described. We present a different perspective of SCID that is managed in a low-middle income country with lack of resources for definitive therapy.
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.
