DeCure for T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency
DeCure's autonomous Immuno AI scientist is researching a drug-repurposing hypothesis for T-B+ severe combined immunodeficiency due to IL-7Ralpha 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 moduleT-B+ severe combined immunodeficiency due to IL-7Ralpha 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 t-b+ severe combined immunodeficiency due to il-7ralpha 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
interleukin 7 receptor (IL7R) — IL7R 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 ngadrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3UP1 · 2.15 Å · ligand 2-acetamido-2-deoxy-beta-D-galactopyranose (NGA). Experimental structure, not a prediction.
What the evidence adds up to
IL-7Ralpha deficiency is a recognised cause of T-B+NK+ severe combined immunodeficiency. A review of 16 novel patients discusses the clinical and immunological features and the results of haematopoietic stem cell transplantation, but provides no numerical outcomes for survival or engraftment. One report describes a 22-month-old girl with compound heterozygous IL7RA mutations and absent IL-7 receptor alpha-chain expression on lymphocytes and monocytes. Despite almost absent T cell functions, her first pneumonia occurred at 9 months and she was successfully transplanted from a 9/10 matched unrelated donor at 24 months. Another case details a 15-month-old girl with normal lymphocyte count, isolated CD4-penia, absence of naïve T cells, marked hypergammaglobulinaemia, and maternal T cell engraftment; she carried two novel compound heterozygous IL7RA mutations. A 1-year-old patient from consanguineous parents presented with autoimmune haemolytic anaemia from birth and recurrent severe infections, had decreased T cells, defective thymic output, and absent T cell proliferation, and was successfully transplanted using an HLA-matched relative. One year after transplant she had normal reconstitution of donor T cells expressing IL-7Ralpha, increased recent thymic emigrants, and restored T cell proliferative response.
Six adults aged 22 to 59 years from three ancestries, carrying homozygous IL7 loss-of-function variants, had combined immunodeficiency rather than SCID. They showed profound T cell lymphopenia, low T cell receptor excision circles, low recent thymic emigrant and naive CD4+ T cells, and low overall TCR repertoire diversity, indicating impaired thymic output. Proportions of effector memory CD4+ and CD8+ T cells were high, suggesting IL-7-independent homeostatic proliferation. Some T cell subsets, including TCRγδ+ T cells, Th1, Tfh, and Treg, were little affected. Peripheral CD4+ T cells proliferated poorly but produced cytokines normally upon mitogen stimulation. The authors conclude that inherited IL-7 deficiency impairs T cell development less severely and in a more subset-specific manner than IL-7R deficiency, and propose that another IL-7R-binding cytokine, possibly thymic stromal lymphopoietin, governs an IL-7-independent pathway of human T cell development.
A gene therapy study in mice used lentiviral vectors carrying the human IL7R gene to transduce bone marrow from Il7r-/- animals, which were then transplanted into lethally irradiated Il7r-/- recipients. Absolute lymphocyte counts were higher in mice receiving transduced marrow (mean 2555/μL) than untransduced marrow (mean 1410/μL). The proportion of T cells was 4.2-fold and 9.8-fold higher at 1 and 2 months post-transplant. B cells were only seen with one vector (vPGK_DHS_hIL7R): 7.4% of leukocytes versus 1.5% in controls. A reciprocal decrease in Gr1+ cells (neutrophils and monocytes) was seen at two months: 36.5% versus 63%. No significant aberrations in absolute neutrophil count, haemoglobin or platelet count were reported. The authors note that lymphocyte subsets, bone marrow and thymic precursors, and T and B cell function in response to immunisations are still being analysed, and that further evaluation in human IL7R-deficient cells is warranted. What remains missing is a clinical trial of gene therapy in patients, a clear understanding of which IL7R regulatory sequences will avoid ectopic expression and lineage skewing in humans, and a strategy for less toxic conditioning that would allow gene-corrected cells to engraft without the risks of graft-versus-host disease from mismatched donors.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Immunological Reviews · 2005 · 173 citations
Interleukin‐7 receptor α (IL‐7Rα) deficiency: cellular and molecular bases. Analysis of clinical, immunological, and molecular features in 16 novel patients
AbstractAnalysis of gene-targeted mice and patients with severe combined immunodeficiency due to mutations of the alpha chain of the interleukin-7 receptor (IL-7Ralpha) has shown important differences between mice and humans in the role played by IL-7 in lymphoid development. More recently, it has been shown that IL-7Ralpha is also shared by the receptor for another cytokine, thymic stromal lymphopoietin (TSLP). In this review, we discuss recent advances in IL-7- and TSLP-mediated signaling. We also report on the clinical and immunological features of 16 novel patients with IL-7Ralpha deficiency and discuss the results of hematopoietic stem cell transplantation.
Delayed Onset of (Severe) Combined Immunodeficiency (S)CID (T-B+NK+): Complete IL-7 Receptor Deficiency in a 22 Months Old Girl
AbstractBACKGROUND: Usually IL-7 receptor deficiency presents as (T-B+NK+) (Severe) Combined Immunodeficiency (SCID) within the first six months of life. All published IL-7R-deficient patients so far have been diagnosed and received stem cell transplantation within the first year of life. PATIENT AND METHODS: We present a female patient born to non-consanguineous German parents with delayed manifestation. She presented with superinfected dermatitis at 6 months of life and developed a first pneumonia at age 9 months. On admission to our department at 22 months the patient presented with severe T cell lymphopenia. PNEUMOCYSTIS JIROVECI pneumonia was diagnosed from broncho-alveolar lavage fluid. RESULTS: Sequencing of IL7RA in the patient revealed compound heterozygous mutations. FACS analysis showed no expression of IL-7 receptor alpha-chain on the patient's lympho- and monocytes. The patient successfully received haematopoietic stem cell transplantation from a 9/10 matched unrelated donor at age 24 months. CONCLUSION: [corrected] Despite almost absent T cell functions clinical symptoms occurred late compared to previously published patients. Thus even in patients with moderate clinical symptoms and delayed onset a (T-B+NK+) (Severe) Combined Immunodeficiency ((S)CID)) due to missing IL-7 receptor signalling must be considered.
Journal of Clinical Investigation · 2024 · 7 citations · open access
IL-7–dependent and –independent lineages of IL-7R–dependent human T cells
AbstractInfants with biallelic IL7R loss-of-function variants have severe combined immune deficiency (SCID) characterized by the absence of autologous T lymphocytes, but normal counts of circulating B and NK cells (T-B+NK+ SCID). We report 6 adults (aged 22 to 59 years) from 4 kindreds and 3 ancestries (Colombian, Israeli Arab, Japanese) carrying homozygous IL7 loss-of-function variants resulting in combined immunodeficiency (CID). Deep immunophenotyping revealed relatively normal counts and/or proportions of myeloid, B, NK, and innate lymphoid cells. By contrast, the patients had profound T cell lymphopenia, with low proportions of innate-like adaptive mucosal-associated invariant T and invariant NK T cells. They also had low blood counts of T cell receptor (TCR) excision circles, recent thymic emigrant T cells and naive CD4+ T cells, and low overall TCR repertoire diversity, collectively indicating impaired thymic output. The proportions of effector memory CD4+ and CD8+ T cells were high, indicating IL-7-independent homeostatic T cell proliferation in the periphery. Intriguingly, the proportions of other T cell subsets, including TCRγδ+ T cells and some TCRαβ+ T cell subsets (including Th1, Tfh, and Treg) were little affected. Peripheral CD4+ T cells displayed poor proliferation, but normal cytokine production upon stimulation with mitogens in vitro. Thus, inherited IL-7 deficiency impairs T cell development less severely and in a more subset-specific manner than IL-7R deficiency. These findings suggest that another IL-7R-binding cytokine, possibly thymic stromal lymphopoietin, governs an IL-7-independent pathway of human T cell development.
Frontiers in Immunology · 2022 · 7 citations · open access
Diagnosis and Treatment of a Patient With Severe Combined Immunodeficiency Due to a Novel Homozygous Mutation in the IL-7Rα Chain
AbstractThe interleukin-7 receptor (IL-7R) is expressed on lymphoid cells and plays an important role in the development, homeostasis, survival, and proliferation of T cells. Bi-allelic mutations in the IL-7Rα chain abolish T cell development and function resulting in severe combined immunodeficiency disease. In this manuscript, we investigate a 1 year-old patient born to consanguineous parents, who suffered from autoimmune hemolytic anemia since birth associated with recurrent severe infections. Flow cytometric analysis of the patient’s peripheral blood demonstrated elevated numbers of B and NK cells, decreased numbers of T cells, defective thymic output, a predominance of memory T cells, and absent T cell proliferation. Next Generation Sequencing identified a novel homozygous pathogenic mutation in IL7RA (c.379G>A) that resulted in aberrant IL7RA RNA splicing and absent IL-7Rα expression. The patient was successfully transplanted using her HLA-matched relative as donor. One year after transplant, the patient is clinically stable with normal reconstitution of donor T cells that express IL-7Rα, a significant increase in the percentages of recent thymic emigrant and peripheral T cells, normalization of naïve and memory T cells, and restoration of her T cell’s proliferative response. Therefore, using genetic and functional approaches, we identified a novel deleterious mutation in IL-7Rα that results in T - B + NK + phenotype, and report successful hematopoietic stem cell transplantation of the patient. This represents the first bedside-to-bench-and-back case entirely performed on a patient with severe combined immunodeficiency at the American University of Beirut Medical Center.
Frontiers in Immunology · 2019 · 6 citations · open access
Novel Compound Heterozygous Mutations in IL-7 Receptor α Gene in a 15-Month-Old Girl Presenting With Thrombocytopenia, Normal T Cell Count and Maternal Engraftment
AbstractPatients with severe combined immunodeficiency (SCID) exhibit T lymphopenia and profound impairments in cellular and humoral immunity. IL-7 receptor α (IL-7Rα) deficiency is a rare form of SCID usually presenting in the first months of life with severe and opportunistic infections, failure to thrive and high risk of mortality unless treated. Here, we report an atypical and delayed onset of IL7Rα-SCID in a 15-month old girl presenting with thrombocytopenia. Immunological investigations showed a normal lymphocytes count with isolated CD4-penia, absence of naïve T cells, marked hypergammaglobulinemia and maternal T cell engraftment. Targeted next generation sequencing (NGS) revealed two novel compound heterozygous mutations in IL-7Rα gene: c.160T>C (p.S54P) and c.245G>T (p.C82F). The atypical onset and the unusual immunological phenotype expressed by our patient highlights the diagnostic challenge in the field of primary immunodeficiencies (PID) and in particular in SCID patients where prompt diagnosis and therapy greatly affects the survival.
Rescue of Murine IL-7 Receptor Deficiency with Human IL-7 Receptor Gene Therapy
AbstractAbstract In humans, interleukin 7 (IL-7) receptor (IL-7R) deficiency causes approximately 10% of cases of severe combined immunodeficiency (SCID). IL-7R deficient SCID is a T-B+NK+ SCID and is caused by autosomal recessive deficiency of the IL-7R alpha chain gene (IL7R). IL-7R is a heterodimeric receptor comprised of the alpha chain and the IL-2 receptor common gamma chain (IL2RG). In both mouse and human, IL-7R is a marker of the common lymphoid progenitor cell, and IL-7 signaling leads to STAT5 phosphorylation and proliferation of developing T and B cells. Mice lacking IL7R, Il7r -/-, lack both T and B cells (Peschon, JJ, et al. J Exp Med. 1994). T cells do not progress to TCR beta chain rearrangement and B cell development is halted at the pre-pro-B cell stage. Similar to the mouse, IL-7 signaling in humans is required for T cell receptor beta gene rearrangement and T cell maintenance, however humans lacking IL-7R can develop B cells. A prior attempt to rescue murine IL-7R deficiency utilized a retroviral vector (mouse stem cell virus, MSCV), the MSCV retroviral promoter, and the murine Il7r gene (Jiang, Q, et al. Gene Therapy. 2005). This strategy did restore T cells and had variable restoration of B cells. However, retroviral-based gene addition of Il7r led to a myeloproliferative condition with significant neutrophilia and splenomegaly. Transduced bone marrow cells formed myeloid progenitors in response to IL-7 in vitro. We evaluated a novel gene therapy for IL-7R deficient SCID that utilizes the human IL7R gene. To prevent lineage skewing, we sought to limit ectopic expression of IL7R in non-lymphoid cells by utilizing the endogenous enhancers and promoters of IL7R. These sequences were identified as sites of high sequence conservation across species and DNA accessibility/hypersensitivity (DHS) in human lymphocytes. We are testing these sequences alone or in combination with the constitutive phosphoglycerate kinase promoter (PGK) in VSV-G pseudotyped lentiviral vectors (LV): vPGK_DHS_hIL7R and vDHS_hIL7R. Here we present the first data evaluating the ability of the human IL-7R protein to functionally replace the murine IL-7R protein and the ability of IL7R gene addition to rescue the murine Il7r -/- immunodeficient phenotype in vivo. Transduction of Il7r -/- bone marrow cells with IL7R encoding LV rescued the formation of lymphocyte precursors from murine bone marrow cells in colony forming unit (CFU) assays (pre-B CFU with human IL-7), with the most robust response seen with vPGK_DHS_hIL7R. Mouse bone marrow from Il7r -/- animals transduced ex vivo engrafted in lethally irradiated (8 Gy) Il7r -/-oppositegender recipients and there were no significant aberrations in absolute neutrophil count, hemoglobin or platelet count. Absolute lymphocyte counts in mice receiving transduced Il7r -/-bone marrow cells was higher (mean 2555/μL) than in mice receiving untransduced bone marrow (mean 1410/μL). The proportion of leukocytes that were T cells was 4.2-fold and 9.8-fold higher at 1 and 2 months post-transplant, respectively. B cells were only seen in mice receiving vPGK_DHS_hIL7R: 7.4% of leukocytes versus 1.5% in controls. A reciprocal decrease in the fraction of Gr1+ cells (neutrophils and monocytes) was seen at two months post-transplant in transduced marrow recipients compared to untransduced controls: 36.5% versus 63% Gr1+, respectively. Lymphocyte subsets are being further analyzed, bone marrow and thymic lymphoid precursors assessed, and T and B cell function in response to immunizations are in progress. Further evaluation in human derived IL7R deficient human cells is warranted. For individuals with IL-7R deficient SCID, but no HLA matched hematopoietic stem cell (HSC) donor, there is a difficult choice between the risks of GVHD with a mismatched HSC donor and supportive care with the hope of identifying a matched HSC donor in the future. In immunodeficiencies however age and serious infection are both associated with increased mortality (Pai, SY, et al. NJEM. 2014). This novel approach to IL7R gene replacement has the potential to be a therapeutic and expedient option for those without a matched donor. Additionally, this would be an ideal disorder for HSC conditioning with less toxic, HSC-targeted strategies given gene corrected lymphocytes and progenitors will preferentially expand post-transplant. Disclosures Rivella: Disc Medicine: Consultancy, Membership on an entity's Board of Directors or advisory committees; Keros Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; Ionis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; MeiraGTx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forma Theraputics: Consultancy; Incyte: Consultancy.
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.
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