DeCure for Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive
DeCure's autonomous Immuno AI scientist is researching a drug-repurposing hypothesis for severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive — screening already-approved drugs against its 6-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, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive maps to a 6-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, autosomal recessive, t cell-negative, b cell-negative, nk cell-positive 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
adenosine deaminase (ADA) — ADA 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 2r,3s,5rdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3IAR · 1.52 Å · ligand (2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-tetrahydro-2-(hydroxymethyl)furan-3-ol (3D1). Experimental structure, not a prediction.
What the evidence adds up to
No abstract in this set studies severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive. The four abstracts cover Burkitt lymphoma in HIV-positive adults, NKG2A expression in HIV infection, a review of NK cell function in HIV, and Good syndrome (thymoma with hypogammaglobulinaemia). None of these conditions is the specified disease, and no drug is tested in that disease.
In the Burkitt lymphoma trial, 36 patients aged 15–55 with advanced Burkitt lymphoma received six cycles of intensive chemotherapy plus eight doses of rituximab. Nineteen patients (53%) were HIV-infected. Complete remission rates were 88% in HIV-negative and 84% in HIV-positive patients. Two-year overall survival was 82% (95% CI 65–99%) for HIV-negative and 73% (95% CI 54–92%) for HIV-positive patients; two-year disease-free survival was 93% and 87% respectively. HIV-positive patients had more grade 3–4 mucositis (27% vs 7% of cycles) and severe infections (26% vs 8%). The authors concluded intensive immunochemotherapy could be given safely to HIV-infected patients.
The 2007 cross-sectional study of 113 HIV-1-infected and 43 uninfected individuals found that in later HIV stages cytotoxic NK cells were fewer and expressed more NKG2A. The percentage of NKG2A-positive cytotoxic NK cells was 25.6% in those with CD4 >500 cells/µL, 40.9% with CD4 200–500, and 48.3% with CD4 <200. NK-mediated cytotoxicity was lower in AIDS patients. The 2022 review summarises that NK cells in HIV infection show impaired function and negative regulation of other immune cells, though they can kill HIV-infected cells. The 2023 Good syndrome study of nine patients found reduced B cells (undetectable in eight), reduced CD4+ T cells, NK cells, neutrophils, basophils, and expanded TCRγδ+ T cells. Those who developed hypogammaglobulinaemia years after thymoma had a combined immune defect with poorer response to immunoglobulin replacement.
What is missing for the specified severe combined immunodeficiency is any abstract testing a drug in that exact disease. No trial, no patient data, no survival or response rates exist in these papers for that condition. The necessary elements — funding, a trial design that recruits patients with the correct genetic diagnosis, and stratification by mutation type — are absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Cancer · 2008 · 126 citations · open access
High‐dose chemotherapy and immunotherapy in adult Burkitt lymphoma
AbstractBACKGROUND: It has been recognized that cure is possible for human immunodeficiency virus (HIV)-infected patients with Burkitt lymphoma/leukemia (BL) if appropriate chemotherapy is used. The introduction of rituximab in BL therapeutic schemes has been scarcely explored. The outcome and toxicity of HIV-positive patients with BL treated in a rituximab and intensive chemotherapy-based trial was evaluated. METHODS: Thirty-six consecutive patients, 15 to 55 years of age, diagnosed with advanced stage BL were recruited from July 2003 to August 2006, stratified according to HIV infection status and treated with 6 cycles of intensive chemotherapy including 8 doses of rituximab. RESULTS: Nineteen of the patients (53%) were HIV-infected. Their clinical characteristics were comparable to those of the HIV-negative patients. Complete remission (CR) rates were 88% and 84%, respectively, for HIV-negative and -positive patients. Twenty-seven patients (82% and 68%, respectively, for HIV-negative and -positive patients) completed the 6 protocol scheduled cycles. HIV-infected patients presented higher incidences of grade 3-4 mucositis (27% vs 7% of cycles, P = .0005) and severe infectious episodes (26% vs 8%, P = .0025). However, there were no statistically significant differences in 2-year overall survival (82%, 95% confidence interval [CI], 65%-99% and 73%, 95% CI, 54%-92%, respectively) or 2-year disease-free survival (93%, 95% CI, 82%-99% and 87%, 95% CI 72%-99%, respectively). CONCLUSIONS: Intensive immunochemotherapy can be administered safely to patients with HIV infection. Despite a higher incidence of severe mucositis and infections the remission and survival rates are comparable to those observed in HIV-negative patients.
Increased NKG2A found in cytotoxic natural killer subset in HIV-1 patients with advanced clinical status
AbstractOBJECTIVES: To investigate the expression of NKG2A on cytotoxic natural killer (NK) cells in HIV-1-infected patients. DESIGN: A cross-sectional study was conducted to investigate the NKG2A expression on NK cell subsets among HIV-infected individuals at different clinical stages and HIV negative controls. METHODS: 113 HIV-1 infected and 43 uninfected individuals were enrolled in this study. The HIV-1 infected patients were further categorized into three groups, CD4 cell count > 500 cells/microl (n = 44), CD4 cell count of 200-500 cells/microl (n = 49) and CD4 cell count < 200 cells/microl (n = 20). Flow cytometry was used to determine the expression of NKG2A on NK cell subsets. A flow-based assay was employed to quantify the NK cytotoxicity. RESULTS: Fewer cytotoxic NK cells and more dysfunctional NK cells were observed in patients with advanced clinical conditions. Higher NKG2A expression level in cytotoxic NK subset were found in later stages HIV infection, 25.6% in groups with CD4 cell count > 500 cells/microl, 40.9% in groups with CD4 cell count 200-500 cells/microl and 48.3% in groups with CD4 cell count < 200 cells/microl. Lower NK mediated cytotoxicity, which was associated with the decrease in cytotoxic NK cell number and higher NKG2A expression on cytotoxic NK subsets, was found in AIDS patients compared with patients at early stage of infection. A reverse association between the percentage of NKG2A positive cells in cytotoxic NK subset and CD4 cell count was observed in all HIV-1 infected groups. CONCLUSION: Fewer cytotoxic NK cells and higher NKG2A expression in cytotoxic NK subset was found in patients in late stage HIV infection. Such a phenomenon may relate to the escape of HIV-1-infected CD4+ T cells from being attacked by NK cells.
Frontiers in Immunology · 2022 · 13 citations · open access
Negative Regulation and Protective Function of Natural Killer Cells in HIV Infection: Two Sides of a Coin
AbstractNatural killer (NK) cells play an important immunologic role, targeting tumors and virus-infected cells; however, NK cells do not impede the progression of human immunodeficiency virus (HIV) infection. In HIV infection, NK cells exhibit impaired functions and negatively regulate other immune cell responses, although NK cells can kill HIV-infected cells and thereby suppress HIV replication. Considerable recent research has emerged regarding NK cells in the areas of immune checkpoints, negative regulation, antibody-dependent cell-mediated cytotoxicity and HIV reservoirs during HIV infection; however, no overall summary of these factors is available. This review focuses on several important aspects of NK cells in relation to HIV infection, including changes in NK cell count, subpopulations, and immune checkpoints, as well as abnormalities in NK cell functions and NK cell negative regulation. The protective function of NK cells in inhibiting HIV replication to reduce the viral reservoir and approaches for enhancing NK cell functions are also summarized.
Frontiers in Immunology · 2023 · 8 citations · open access
In-depth blood immune profiling of Good syndrome patients
AbstractIntroduction Good syndrome (GS) is a rare adult-onset immunodeficiency first described in 1954. It is characterized by the coexistence of a thymoma and hypogammaglobulinemia, associated with an increased susceptibility to infections and autoimmunity. The classification and management of GS has been long hampered by the lack of data about the underlying immune alterations, a controversy existing on whether it is a unique diagnostic entity vs . a subtype of Common Variable Immune Deficiency (CVID). Methods Here, we used high-sensitive flow cytometry to investigate the distribution of up to 70 different immune cell populations in blood of GS patients (n=9) compared to age-matched CVID patients (n=55) and healthy donors (n=61). Results All 9 GS patients displayed reduced B-cell counts -down to undetectable levels (&lt;0.1 cells/μL) in 8/9 cases-, together with decreased numbers of total CD4 + T-cells, NK-cells, neutrophils, and basophils vs. age-matched healthy donors. In contrast, they showed expanded TCRγδ + T-cells (p ≤ 0.05). Except for a deeper B-cell defect, the pattern of immune cell alteration in blood was similar in GS and (age-matched) CVID patients. In depth analysis of CD4 + T-cells revealed significantly decreased blood counts of naïve, central memory (CM) and transitional memory (TM) TCD4 + cells and their functional compartments of T follicular helper (TFH), regulatory T cells (Tregs), T helper (Th)2, Th17, Th22, Th1/Th17 and Th1/Th2 cells. In addition, GS patients also showed decreased NK-cell, neutrophil, basophil, classical monocyte and of both CD1c + and CD141 + myeloid dendritic cell counts in blood, in parallel to an expansion of total and terminal effector TCRγδ + T-cells. Interestingly, those GS patients who developed hypogammaglobulinemia several years after the thymoma presented with an immunological and clinical phenotype which more closely resembled a combined immune humoral and cellular defect, with poorer response to immunoglobulin replacement therapy, as compared to those in whom the thymoma and hypogammaglobulinemia were simultaneously detected. Discussion Our findings provide a more accurate definition of the immune cell defects of GS patients and contribute to a better discrimination among GS patients between those with a pure B-cell defect vs . those suffering from a combined immunodeficiency with important consequences on the diagnosis and management of the disease.
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.
