DeCure for Combined immunodeficiency due to ZAP70 deficiency
DeCure's autonomous Immuno AI scientist is researching a drug-repurposing hypothesis for combined immunodeficiency due to ZAP70 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 moduleCombined immunodeficiency due to ZAP70 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 combined immunodeficiency due to zap70 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
zeta chain of T cell receptor associated protein kinase 70 (ZAP70) — ZAP70 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 anpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2OZO · 2.6 Å · ligand PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER (ANP). Experimental structure, not a prediction.
What the evidence adds up to
ZAP-70 deficiency is a rare combined immunodeficiency caused by recessive loss-of-function mutations in the ZAP70 gene. A systematic review of 49 patients identified from 33 articles reported that the predominant immunologic phenotype was low CD8+ T cell counts, found in 97.9% of patients. Defective antibody production was seen in 57% of patients, and decreased lymphocyte responses to the mitogen phytohemagglutinin occurred in 95%. The most frequent clinical manifestations were recurrent respiratory infections (81.8%) and cutaneous involvement (57.9%), followed by lymphoproliferation (32.4%), autoimmunity (19.4%), enteropathy (18.4%), and malignancy (8.1%). Mutations were distributed throughout the ZAP70 gene with no mutational hotspot, though most were located in the kinase domain; the splice site mutation c.1624-11G>A (p.K541_K542insLEQ) was the most common, found in 10 families. No genotype-phenotype correlation was observed.
Hematopoietic stem cell transplantation (HSCT) was applied as the major curative treatment in 25 of the 49 patients (51%). Of those transplanted, 18 survived, two died, and three required a second transplant to achieve full remission. A separate case report described a 7-month-old infant initially misdiagnosed with incomplete Kawasaki disease, who later presented with failure to thrive and varicella infection following vaccination; flow cytometry showed nearly absent CD8+ T cells with a CD4+/CD8+ ratio of 40:1, and absent ZAP70 expression on T cells and NK cells. That patient was doing well with minor graft-versus-host disease two years after bone marrow transplantation. Another case from the National Iranian Registry described a 3-year-old boy with recurrent bacterial infections, autoimmunity, low CD8 and CD4 T cells, and impaired specific antibody responses despite normal immunoglobulin levels; whole exome sequencing revealed a mutation in the kinase domain of ZAP70.
The evidence is limited to small case series and individual reports, with no controlled trials. The systematic review pooled only 49 patients from the literature, and the two versions of that review give slightly different percentages for some clinical features (e.g., respiratory infections 61.2% vs 81.8%), suggesting inconsistency in the underlying data. What is still missing is a prospective registry or clinical trial that could standardise diagnostic criteria, stratify patients by mutation type and age at transplant, and track long-term outcomes beyond the small numbers currently available. No drug therapy has been tested in these patients; HSCT remains the only reported curative intervention, and its success rate is based on fewer than 30 treated individuals.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Frontiers in Immunology · 2020 · 50 citations · open access
Clinical, Immunological, and Genetic Features in 49 Patients With ZAP-70 Deficiency: A Systematic Review
AbstractBackground: Zeta-Chain Associated Protein Kinase 70 kDa (ZAP-70) deficiency is a novel combined immunodeficiency (CID) caused by recessive homozygous/compound heterozygous loss-of-function mutations in the ZAP70 gene. Patients with ZAP-70 deficiency present with a variety of clinical manifestations, particularly recurrent respiratory infections and cutaneous involvements. Methods: We searched PubMed, Web of Science, and Scopus databases for all reported ZAP-70 deficient patients and screened against the described eligibility criteria. A total of 49 ZAP-70 deficient patients were identified from 86 articles. For all patients, demographic, clinical, immunologic, and molecular data were collected. Results: ZAP-70 deficient patients have been reported in the literature with a broad spectrum of clinical manifestations including recurrent respiratory infections (61.2%), cutaneous involvement (44.9%), lymphoproliferation (24.5%), autoimmunity (14.3%), enteropathy (14.3%), and increased risk of malignancies (6.1%). The predominant immunologic phenotype was low CD8+ T cell counts (89.8%). Immunologic profiling showed defective antibody production (>60%) and decreased lymphocyte responses to mitogenic stimuli such as phytohemagglutinin (89.7%). Mutations of the ZAP70 gene were located throughout the gene, and there was no mutational hot spot. However, the splice site mutation c.1624-11G>A (p.K541_K542insLEQ), located in the kinase domain, was the most frequent mutation (found in 10 families). Hematopoietic stem cell transplantation (HSCT) was applied as the major curative treatment in 25 (51%) of the patients, 18 patients survived transplantation, while two patients died and three required a second transplant in order to achieve full remission. Conclusion: Newborns with consanguineous parents, positive family history of CID, and low CD8+ T cell counts should be considered for ZAP-70 deficiency screening, since early diagnosis and treatment with HSCT can lead to a more favorable outcome. Based on the current evidence, there is no genotype-phenotype correlation in ZAP-70 deficient patients.
Novel Mutation of ZAP-70-related Combined Immunodeficiency: First Case from the National Iranian Registry and Review of the Literature
AbstractZAP-70 deficiency is a rare autosomal recessive form of combined immunodeficiency (CID) characterized by selective absence of circulating CD8 T cells with low, normal, or increased CD4 T cells in peripheral blood. Up to now, 14 unique mutations in the ZAP70 gene have been identified in patients with ZAP-70-related CID. We present a 3-year-old boy with a history of recurrent bacterial infections and autoimmunity. Initial laboratory findings showed a normal total lymphocyte count, but low levels of CD8 and CD4 T cells and an abnormal lymphocyte proliferation response. Immunoglobulin levels were normal, but the specific antibody response was impaired. Whole exome sequencing revealed a mutation within the kinase domain of ZAP-70. ZAP-70 deficiency should be considered in infants and young children with recurrent bacterial infections, in spite of having palpable lymph nodes, a notable thymus shadow, and a normal total lymphocyte count.
Zenodo (CERN European Organization for Nuclear Research) · 2017 · 1 citations · open access
ZAP70 Related Severe Combined Immunodeficiency Initially Diagnosed as Incomplete (Atypical) Kawasaki Disease
AbstractZAP70-related severe combined immunodeficiency (SCID) is a defect of the immune system characterized by absent or extremely low CD8+ T-cells and abnormal T-cell receptor signaling. This form of SCID is relatively rare with about 20 cases currently described in the literature and typically presents in infancy with recurrent opportunistic infections, failure to thrive, and gastrointestinal symptoms. This report describes a case of ZAP70-related SCID that was initially diagnosed as incomplete (atypical) Kawasaki disease. A 7-month-old infant presented with two weeks of fever, leukocytosis (33.5 K/μL) and anemia. No infectious etiology was identified and clinical presentation, along with laboratory work-up, suggested incomplete Kawasaki disease. He was treated with a single infusion of IVIG and 72 hours of high dose aspirin with resolution of fever. Seven months later, he presented again with three weeks of fever, persistent leukocytosis, failure to thrive and varicella infection following vaccination. During hospital admission, flow cytometric analysis was conducted to characterize atypical lymphocytes present in peripheral blood. The results revealed nearly absent CD8+ T-cells with a CD4+/CD8+ ratio of 40:1. Subsequent studies demonstrated the absence of ZAP70 expression on T-cells and NK-cells by flow cytometry. Additional testing revealed markedly decreased to absent CD45+ total lymphocyte proliferative response to mitogens and antigens. The patient was diagnosed with ZAP70-related SCID and was referred for further evaluation and bone marrow transplantation. He is currently doing well, apart from minor GVHD, 2 years post-transplant.
Table_1_Clinical, Immunological, and Genetic Features in 49 Patients With ZAP-70 Deficiency: A Systematic Review.pdf
Abstract<p>Background: Zeta-Chain Associated Protein Kinase 70 kDa (ZAP-70) deficiency is a rare combined immunodeficiency (CID) caused by recessive homozygous/compound heterozygous loss-of-function mutations in the ZAP70 gene. Patients with ZAP-70 deficiency present with a variety of clinical manifestations, particularly recurrent respiratory infections and cutaneous involvements. Therefore, a systematic review of ZAP-70 deficiency is helpful to achieve a comprehensive view of this disease.</p><p>Methods: We searched PubMed, Web of Science, and Scopus databases for all reported ZAP-70 deficient patients and screened against the described eligibility criteria. A total of 49 ZAP-70 deficient patients were identified from 33 articles. For all patients, demographic, clinical, immunologic, and molecular data were collected.</p><p>Results: ZAP-70 deficient patients have been reported in the literature with a broad spectrum of clinical manifestations including recurrent respiratory infections (81.8%), cutaneous involvement (57.9%), lymphoproliferation (32.4%), autoimmunity (19.4%), enteropathy (18.4%), and increased risk of malignancies (8.1%). The predominant immunologic phenotype was low CD8+ T cell counts (97.9%). Immunologic profiling showed defective antibody production (57%) and decreased lymphocyte responses to mitogenic stimuli such as phytohemagglutinin (PHA) (95%). Mutations of the ZAP70 gene were located throughout the gene, and there was no mutational hotspot. However, most of the mutations were located in the kinase domain. Hematopoietic stem cell transplantation (HSCT) was applied as the major curative treatment in 25 (51%) of the patients, 18 patients survived transplantation, while two patients died and three required a second transplant in order to achieve full remission.</p><p>Conclusion: Newborns with consanguineous parents, positive family history of CID, and low CD8+ T cell counts should be considered for ZAP-70 deficiency screening, since early diagnosis and treatment with HSCT can lead to a more favorable outcome. Based on the current evidence, there is no genotype-phenotype correlation in ZAP-70 deficient patients.</p>
Image_1_Clinical, Immunological, and Genetic Features in 49 Patients With ZAP-70 Deficiency: A Systematic Review.pdf
Abstract<p>Background: Zeta-Chain Associated Protein Kinase 70 kDa (ZAP-70) deficiency is a rare combined immunodeficiency (CID) caused by recessive homozygous/compound heterozygous loss-of-function mutations in the ZAP70 gene. Patients with ZAP-70 deficiency present with a variety of clinical manifestations, particularly recurrent respiratory infections and cutaneous involvements. Therefore, a systematic review of ZAP-70 deficiency is helpful to achieve a comprehensive view of this disease.</p><p>Methods: We searched PubMed, Web of Science, and Scopus databases for all reported ZAP-70 deficient patients and screened against the described eligibility criteria. A total of 49 ZAP-70 deficient patients were identified from 33 articles. For all patients, demographic, clinical, immunologic, and molecular data were collected.</p><p>Results: ZAP-70 deficient patients have been reported in the literature with a broad spectrum of clinical manifestations including recurrent respiratory infections (81.8%), cutaneous involvement (57.9%), lymphoproliferation (32.4%), autoimmunity (19.4%), enteropathy (18.4%), and increased risk of malignancies (8.1%). The predominant immunologic phenotype was low CD8+ T cell counts (97.9%). Immunologic profiling showed defective antibody production (57%) and decreased lymphocyte responses to mitogenic stimuli such as phytohemagglutinin (PHA) (95%). Mutations of the ZAP70 gene were located throughout the gene, and there was no mutational hotspot. However, most of the mutations were located in the kinase domain. Hematopoietic stem cell transplantation (HSCT) was applied as the major curative treatment in 25 (51%) of the patients, 18 patients survived transplantation, while two patients died and three required a second transplant in order to achieve full remission.</p><p>Conclusion: Newborns with consanguineous parents, positive family history of CID, and low CD8+ T cell counts should be considered for ZAP-70 deficiency screening, since early diagnosis and treatment with HSCT can lead to a more favorable outcome. Based on the current evidence, there is no genotype-phenotype correlation in ZAP-70 deficient patients.</p>
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.
