DeCure for Combined immunodeficiency due to DOCK8 deficiency
DeCure's autonomous Immuno AI scientist is researching a drug-repurposing hypothesis for combined immunodeficiency due to DOCK8 deficiency — screening already-approved drugs against its 2-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 DOCK8 deficiency maps to a 2-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 dock8 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
serine/threonine kinase 4 (STK4) — STK4 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 fluoranyldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8PAV · 1.9 Å · ligand 1-[3,5-bis(fluoranyl)-4-[[3-(1,3-thiazol-5-yl)-1~{H}-pyrrolo[2,3-b]pyridin-4-yl]oxy]phenyl]-3-(2-methoxyethyl)urea (XOZ). Experimental structure, not a prediction.
What the evidence adds up to
DOCK8 immunodeficiency syndrome is a combined immunodeficiency defined by recurrent viral infections, severe atopy, and early onset malignancy. Clinical markers include atopic dermatitis, allergies, cutaneous viral infections, recurrent respiratory tract infections, and malignancy. Laboratory findings show T cell lymphopenia, hyper-IgE, hypo-IgM, and eosinophilia. The DOCK8 locus contains many repetitive sequence elements that predispose to large germline deletions and recombination-mediated somatic DNA repair. Residual DOCK8 protein contributes to variable disease phenotype. One case report described an 8-year-old girl with two novel variants — one deletion and one premature stop codon — resulting in markedly reduced but not absent DOCK8 expression, with somatic reversion identified in T cells. This patient had a restricted T cell repertoire, decreased STAT5 phosphorylation, and impaired immune synapse functioning. Despite an incomplete phenotype without markedly elevated IgE or eosinophil count, sclerosing cholangitis was incidentally detected, indicating that hypomorphic function and somatic reversion may delay but not prevent severe complications.
Hematopoietic stem cell transplantation (HSCT) has been reported as a curative approach. A 2025 case report described a 6-year-old girl who underwent haploidentical HSCT from her father and achieved full donor chimerism with significant improvement in skin condition. An earlier review noted that HSCT cures eczema and infection susceptibility but not necessarily other manifestations including food allergies. The disease is progressive, and the severe virus infections of the skin, along with VZV-associated vasculopathy, reflect DOCK8's role in maintaining lymphocyte shape integrity during migration through dense tissues. Additional immune deficits arise from a milder generalized cell survival defect, skewing of T helper cell subsets, and impaired dendritic cell and regulatory T cell responses.
No drug therapy has been shown to alter the underlying immunodeficiency. All reported interventions are transplant-based, and no controlled trials of any pharmacological agent for DOCK8 deficiency were found in these abstracts. What remains missing is any randomised trial of drug treatment, systematic data on whether partial DOCK8 function can be therapeutically augmented, and patient stratification by residual protein expression and somatic reversion status.
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 · 2009 · 735 citations · open access
Combined Immunodeficiency Associated with <i>DOCK8</i> Mutations
AbstractBACKGROUND: Recurrent sinopulmonary and cutaneous viral infections with elevated serum levels of IgE are features of some variants of combined immunodeficiency. The genetic causes of these variants are unknown. METHODS: We collected longitudinal clinical data on 11 patients from eight families who had recurrent sinopulmonary and cutaneous viral infections. We performed comparative genomic hybridization arrays and targeted gene sequencing. Variants with predicted loss-of-expression mutations were confirmed by means of a quantitative reverse-transcriptase-polymerase-chain-reaction assay and immunoblotting. We evaluated the number and function of lymphocytes with the use of in vitro assays and flow cytometry. RESULTS: Patients had recurrent otitis media, sinusitis, and pneumonias; recurrent Staphylococcus aureus skin infections with otitis externa; recurrent, severe herpes simplex virus or herpes zoster infections; extensive and persistent infections with molluscum contagiosum; and human papillomavirus infections. Most patients had severe atopy with anaphylaxis; several had squamous-cell carcinomas, and one had T-cell lymphoma-leukemia. Elevated serum IgE levels, hypereosinophilia, low numbers of T cells and B cells, low serum IgM levels, and variable IgG antibody responses were common. Expansion in vitro of activated CD8 T cells was impaired. Novel homozygous or compound heterozygous deletions and point mutations in the gene encoding the dedicator of cytokinesis 8 protein (DOCK8) led to the absence of DOCK8 protein in lymphocytes. CONCLUSIONS: Autosomal recessive DOCK8 deficiency is associated with a novel variant of combined immunodeficiency.
Genetic, clinical, and laboratory markers for DOCK8 immunodeficiency syndrome.
AbstractDOCK8 immunodeficiency syndrome (DIDS) is a combined immunodeficiency characterized by recurrent viral infections, severe atopy, and early onset malignancy. Genetic studies revealed large, unique deletions in patients from different families and ethnic backgrounds. Clinical markers of DIDS include atopic dermatitis, allergies, cutaneous viral infections, recurrent respiratory tract infections, and malignancy. Immune assessments showed T cell lymphopenia, hyper-IgE, hypo-IgM, and eosinophilia. The impaired lymphocyte functions in DIDS patients appear central for disease pathogenesis.
Insights into immunity from clinical and basic science studies of <scp>DOCK</scp>8 immunodeficiency syndrome
AbstractDOCK8 immunodeficiency syndrome (DIDS) is a progressive combined immunodeficiency that can be distinguished from other combined immunodeficiencies or hyperimmunoglobulinemia E syndromes in featuring (a) profound susceptibility to virus infections of the skin, with associated skin cancers, and (b) severe food allergies. The DOCK8 locus has many repetitive sequence elements that predispose to the generation of large germline deletions as well as recombination-mediated somatic DNA repair. Residual DOCK8 protein contributes to the variable disease phenotype. The severe virus infections of the skin, and probably also VZV-associated vasculopathy, reflect an important function of DOCK8, which is normally required to maintain lymphocyte shape integrity as the cells migrate through dense tissues. Loss of DOCK8 also causes immune deficits through other mechanisms including a milder generalized cell survival defect and skewing of T helper cell subsets. Recent work has uncovered the roles for DOCK8 in dendritic cell responses that can also help explain the virus susceptibility, as well as in regulatory T cells that might help explain autoimmunity in a minority of patients. Fortunately, hematopoietic stem cell transplantation cures the eczema and infection susceptibility of DIDS, but not necessarily the other disease manifestations including food allergies.
Disease Markers · 2010 · 71 citations · open access
Genetic, Clinical, and Laboratory Markers for DOCK8 Immunodeficiency Syndrome
AbstractDOCK8 immunodeficiency syndrome (DIDS) is a combined immunodeficiency characterized by recurrent viral infections, severe atopy, and early onset malignancy. Genetic studies revealed large, unique deletions in patients from different families and ethnic backgrounds. Clinical markers of DIDS include atopic dermatitis, allergies, cutaneous viral infections, recurrent respiratory tract infections, and malignancy. Immune assessments showed T cell lymphopenia, hyper-IgE, hypo-IgM, and eosinophilia. The impaired lymphocyte functions in DIDS patients appear central for disease pathogenesis.
Frontiers in Immunology · 2021 · 7 citations · open access
Case Report: Hypomorphic Function and Somatic Reversion in DOCK8 Deficiency in One Patient With Two Novel Variants and Sclerosing Cholangitis
AbstractDOCK8 deficiency is a combined immunodeficiency due to biallelic variants in dedicator of cytokinesis 8 ( DOCK8 ) gene. The disease has a wide clinical spectrum encompassing recurrent infections (candidiasis, viral and bacterial infections), virally driven malignancies and immune dysregulatory features, including autoimmune (cytopenia and vasculitis) as well as allergic disorders (eczema, asthma, and food allergy). Hypomorphic function and somatic reversion of DOCK8 has been reported to result in incomplete phenotype without IgE overproduction. Here we describe a case of DOCK8 deficiency in a 8-year-old Caucasian girl. The patient’s disease was initially classified as autoimmune thrombocytopenia, which then evolved toward a combined immunodeficiency phenotype with recurrent infections, persistent EBV infection and lymphoproliferation. Two novel variants (one deletion and one premature stop codon) were characterized, resulting in markedly reduced, but not absent, DOCK8 expression. Somatic reversion of the DOCK8 deletion was identified in T cells. Hypomorphic function and somatic reversion were associated with restricted T cell repertoire, decreased STAT5 phosphorylation and impaired immune synapse functioning in T cells. Although the patient presented with incomplete phenotype (absence of markedly increase IgE and eosinophil count), sclerosing cholangitis was incidentally detected, thus indicating that hypomorphic function and somatic reversion of DOCK8 may delay disease progression but do not necessarily prevent from severe complications.
Haploidentical stem cell transplantation in DOCK8 deficiency: a case report of successful outcomes
AbstractDOCK8 deficiency syndrome, formerly known as autosomal recessive hyper-IgE syndrome (AR-HIES), is a rare combined immunodeficiency disorder characterized by recurrent infections, eczema, eosinophilia, and elevated immunoglobulin E (IgE) levels. We present a case of a 6-year-old girl with DOCK8 deficiency syndrome, who experienced recurrent skin infections and molluscum contagiosum since infancy. Genetic testing confirmed the diagnosis. Due to the high morbidity and mortality associated with DOCK8 deficiency syndrome, she underwent hematopoietic stem cell transplantation (HSCT) from her father. Posttransplant, the patient's skin condition significantly improved, and she achieved full donor chimerism. This case highlights the importance of considering DOCK8 deficiency in patients with recurrent infections, eczema, eosinophilia, and high IgE levels, and the potential curative effect of HSCT for these patients.
Addison-Wesley Professional eBooks · 2006 · 0 citations
A Developer's Guide to SQL Server 2005 (Microsoft .NET Development Series)
AbstractDOCK8 immunodeficiency syndrome (DIDS) is a combined immunodeficiency characterized by recurrent viral infections, severe atopy, and early onset malignancy. Genetic studies revealed large, unique deletions in patients from different families and ethnic backgrounds. Clinical markers of DIDS include atopic dermatitis, allergies, cutaneous viral infections, recurrent respiratory tract infections, and malignancy. Immune assessments showed T cell lymphopenia, hyper-IgE, hypo-IgM, and eosinophilia. The impaired lymphocyte functions in DIDS patients appear central for disease pathogenesis.
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.
