DeCure for Combined immunodeficiency due to ORAI1 deficiency
DeCure's autonomous Immuno AI scientist is researching a drug-repurposing hypothesis for combined immunodeficiency due to ORAI1 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 ORAI1 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 orai1 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.
What the evidence adds up to
ORAI1 deficiency is a primary immunodeficiency caused by loss-of-function mutations in the pore-forming subunit of the CRAC channel. In a 2010 study using Orai1 knock-in mice expressing the nonfunctional ORAI1-R93W protein, homozygous mice died neonatally, but fetal liver chimeric mice were viable and showed normal lymphocyte development. T and B cells from these mice displayed severely impaired store-operated calcium entry and CRAC channel function, resulting in strongly reduced expression of several key cytokines including IL-2, IL-4, IL-17, IFN-γ, and TNF-α in CD4+ and CD8+ T cells. In vivo cell-mediated immune responses dependent on Th1, Th2, and Th17 function were severely attenuated. Orai1-deficient mice lacked detectable contact hypersensitivity responses and tolerated skin allografts significantly longer than wild-type mice. T cells from these mice also failed to induce colitis in an adoptive transfer model of inflammatory bowel disease.
A 2009 pilot study tested a combination of interferon alpha and azidothymidine in six patients with chronic hepatitis B and concurrent HIV infection. None of the patients lost hepatitis B virus, and HBV-DNA concentrations were not significantly influenced by treatment. HIV infection was also not affected except for a transient rise in CD4-positive cells in two individuals who had initially low CD4-positive cells. Treatment did not influence the presence of HIV antigen in serum. The authors concluded that this combination therapy did not appear beneficial at the doses given and over the four-month treatment period.
A 2015 classification update from the International Union of Immunological Societies listed 34 new gene defects in primary immunodeficiencies since the previous version two years earlier. The report noted increasing overlap between immunodeficiency, manifested by infection and/or malignancy, and immune dysregulation, manifested by auto-inflammation, auto-immunity, and/or allergy. An increased number of genetic defects leading to susceptibility to specific organisms was also observed.
What remains missing for ORAI1 deficiency specifically are clinical trials of any drug in affected patients. The mouse model data confirm the channel's critical role in T cell function but no human treatment study for this condition was found. No drug has been tested in ORAI1-deficient patients. The interferon and azidothymidine study involved a different disease entirely and showed no benefit. Funding for drug development in ultra-rare immunodeficiencies, appropriate trial design for very small patient populations, and patient stratification by residual channel function are all 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.
The Journal of Immunology · 2010 · 145 citations · open access
Store-Operated Ca2+ Entry through ORAI1 Is Critical for T Cell-Mediated Autoimmunity and Allograft Rejection
AbstractORAI1 is the pore-forming subunit of the Ca(2+) release-activated Ca(2+) (CRAC) channel, which is responsible for store-operated Ca(2+) entry in lymphocytes. A role for ORAI1 in T cell function in vivo has been inferred from in vitro studies of T cells from human immunodeficient patients with mutations in ORAI1 and Orai1(-/-) mice, but a detailed analysis of T cell-mediated immune responses in vivo in mice lacking functional ORAI1 has been missing. We therefore generated Orai1 knock-in mice (Orai1(KI/KI)) expressing a nonfunctional ORAI1-R93W protein. Homozygosity for the equivalent ORAI1-R91W mutation abolishes CRAC channel function in human T cells resulting in severe immunodeficiency. Homozygous Orai1(KI/KI) mice die neonatally, but Orai1(KI/KI) fetal liver chimeric mice are viable and show normal lymphocyte development. T and B cells from Orai1(KI/KI) mice display severely impaired store-operated Ca(2+) entry and CRAC channel function resulting in a strongly reduced expression of several key cytokines including IL-2, IL-4, IL-17, IFN-γ, and TNF-α in CD4(+) and CD8(+) T cells. Cell-mediated immune responses in vivo that depend on Th1, Th2, and Th17 cell function were severely attenuated in ORAI1-deficient mice. Orai1(KI/KI) mice lacked detectable contact hypersensitivity responses and tolerated skin allografts significantly longer than wild-type mice. In addition, T cells from Orai1(KI/KI) mice failed to induce colitis in an adoptive transfer model of inflammatory bowel disease. These findings reaffirm the critical role of ORAI1 for T cell function and provide important insights into the in vivo functions of CRAC channels for T cell-mediated immunity.
Treatment of Patients with Chronic Type B Hepatitis and Concurrent Human Immunodeficiency Virus Infection with a Combination of Interferon Alpha and Azidothymidine: A Pilot Study
AbstractSix patients with chronic type B hepatitis and concurrent infection with the immunodeficiency virus were treated with 600 mg azidothymidine (AZT)/day and 3 X 10(6) units of interferon-alpha (IFN-alpha) every other day for a total of 4 months. None of the patients treated lost the hepatitis B virus (HBV). HBV-DNA concentrations were not significantly influenced by this treatment. Human immunodeficiency virus (HIV) infection was also not affected except for a transient rise in CD 4-positive cells in 2 individuals, who had initially low CD 4-positive cells. Treatment did not influence the presence of HIV-Ag in the serum. In conclusion, a combination therapy of IFN and AZT does not seem to be beneficial at the doses given and the time involved.
Greater South Information System · 2015 · 0 citations · open access
Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015
AbstractWe report the updated classification of primary immunodeficiencies compiled by the Primary Immunodeficiency Expert Committee (PID EC) of the International Union of Immunological Societies (IUIS). In the two years since the previous version, 34 new gene defects are reported in this updated version. For each disorder, the key clinical and laboratory features are provided. In this new version we continue to see the increasing overlap between immunodeficiency, as manifested by infection and/or malignancy, and immune dysregulation, as manifested by auto-inflammation, auto-immunity, and/or allergy. There is also an increased number of genetic defects that lead to susceptibility to specific organisms which reflects the finely tuned nature of immune defense systems. This classification is the most up to date catalogue of all known and published primary immunodeficiencies and acts as a current reference of the knowledge of these conditions and is an important aid for the genetic and molecular diagnosis of patients with these rare diseases.
Zenodo (CERN European Organization for Nuclear Research) · 2025 · 0 citations · open access
Selective Immunoglobulin Deficiency in Patients Treated with Lithium: Clinical and Immunological Insights
AbstractObjective: To analyze the association between chronic lithium treatment and selective immunoglobulin deficiency, exploring pathophysiological mechanisms, clinical consequences, and monitoring strategies. Methods: Observational data from patients on long-term lithium therapy were combined with a review of the literature. Results: Lithium exposure was associated with reductions in immunoglobulin levels, particularly IgG and IgA, predisposing to recurrent infections and altered immune responses. Conclusion: Immunoglobulin deficiency should be considered an underrecognized complication of lithium therapy, requiring routine immunological monitoring and individualized management strategies.
Immunology and Genetics Journal · 2022 · 0 citations
Descriptive Study of 123 Symptomatic Patients with IgA Deficiency, a Retrospective Case Series Study
AbstractBackground: IgA deficiency (IgAD) is the most common primary immunodeficiency, which is caused by a defect in IgA antibody production. Most of the patients are asymptomatic. However, patients can present various manifestations. This study was designed to assess the clinical and laboratory manifestations of symptomatic patients with IgA deficiency. Method: A group of 123 patients with IgA deficiency referred from all over the country to the national immunodeficiency registration center were entered and followed in this study. The data including demographic characteristics, clinical manifestations and laboratory findings recorded at the registry and also the follow-up visits were extracted. Results: The mean age of studied patients was 17.1 years old. Regarding gender, 45 patients (36.5%) were female. The most common clinical presentations included upper respiratory tract infections in 22 (17.9%), enteropathy in 9 (7.9%), allergic rhinitis in 11 (8.9%), sepsis in 4 (3.3%) patients. Four cases of leukopenia with white blood cell (WBC) <4,000/μl and 21 cases of leukocytosis with WBC> 10,000/μl were observed based on the laboratory results. Moreover, IgG2 and IgG4 in 2 and 11 patients were less than normal rate for their age, respectively. Conclusion: Although IgA deficient patients are almost always asymptomatic, clinical manifestations such as recurrent sinopulmonary infections, multiple autoimmune diseases, allergic respiratory and skin disorders, gastrointestinal diseases, and rarely severe life-threatening infections could occur.
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.
