DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for MHC class II deficiency — screening already-approved drugs against its 8-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleMHC class II deficiency maps to a 8-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 mhc class ii 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
regulatory factor X associated ankyrin containing protein (RFXANK) — RFXANK 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 unxdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6MEW · 1.78 Å · ligand UNKNOWN ATOM OR ION (UNX). Experimental structure, not a prediction.
What the evidence adds up to
Allogeneic haematopoietic stem cell transplantation (HSCT) is the only curative treatment for MHC class II deficiency. In a series of 30 children who underwent 33 HSCT procedures between 1994 and 2007, median age at transplant was 27 months. Stem cell sources were unmanipulated bone marrow from HLA-identical related donors in 26 patients, one HLA antigen-mismatched bone marrow in 3 patients, and unrelated umbilical cord blood in 1 patient. Conditioning regimens varied: 18 patients received myeloablative busulfan, cyclophosphamide, and etoposide; 2 received busulfan, cyclophosphamide, and antithymocyte globulin; 1 received cyclophosphamide and total body irradiation; and 12 received a reduced-intensity regimen of fludarabine, melphalan, and antithymocyte globulin. The median CD34 cell dose was 8.3 × 10⁶ per kilogram.
Twenty patients achieved immune reconstitution with sustained donor engraftment ranging from 9% to 100% for lymphoid lines and 5% to 100% for myeloid lines, sufficient to cure the disease. Overall disease-free survival was 66%, rising to 76% after HLA-identical HSCT, with a median follow-up of 6.3 years. The authors note this survival rate is higher than previously reported. Both myeloablative and reduced-intensity conditioning achieved reliable donor stem cell engraftment and immune reconstitution in HLA-identical transplant recipients.
A 1995 review describes MHC class II deficiency as a disease of gene regulation involving trans-acting regulatory factors, but provides no treatment data. A 2020 mouse study found that after bone marrow transplantation with T-cell depletion, complete MHC or isolated MHC class II mismatch led to significantly higher graft-versus-host disease scores over time. Without T-cell depletion and with additional donor lymph node cell injection, isolated MHC class II mismatch produced higher GvHD scores than MHC class I mismatch.
What remains missing is a prospective trial comparing conditioning regimens head-to-head in MHC class II deficiency, long-term follow-up data beyond a median of 6.3 years, and any evidence for drug-based therapies that could replace or precede transplantation. No pharmacological treatment has been tested in this patient population.
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 · 2001 · 48 citations · open access
Mutation in the Class II <i>trans-</i> Activator Leading to a Mild Immunodeficiency
AbstractThe expression of MHC class II molecules is essential for all Ag-dependent immune functions and is regulated at the transcriptional level. Four trans-acting proteins control the coordinate expression of MHC class II molecules: class II trans-activator (CIITA), regulatory factor binding to the X box (RFX)-associated protein; RFX protein containing ankyrin repeats, and RFX5. In humans, defects in these genes result in MHC class II expression deficiency and cause combined immunodeficiency. Most patients with this deficiency suffer from severe recurrent infections that frequently lead to death during early childhood. We investigated three sisters, now ages 21, 22, and 24 years, in whom MHC-II deficiency was detected. Even though the eldest sibling was asymptomatic and the other two had only mild immunodeficiency, none of the three class II isotypes was expressed on T cell blasts, fibroblasts, EBV B cell lines, or epidermal dendritic cells. Residual HLA-II expression was detected in fresh PBMC. Somatic complementation identified the disease as CIITA deficiency. A homozygous T1524C (L469P) substitution was found in the coding region of the CIITA cDNA and was shown to be responsible for the defect in MHC-II expression. This missense mutation prevents the normal functioning of MHC-II but does not lead to the nuclear exclusion of the L469P CIITA. Transfection experiments demonstrated that the CIITA L469P mutant had residual MHC class II trans activation activity, which might explain the unusual clinical course of the patients studied. This study shows that an attenuated clinical phenotype or an asymptomatic clinical course can be observed in patients despite a profound defect in the expression of MHC class II genes. The frequency of the inherited MHC class II deficiency might thus be underestimated.
Biology of Blood and Marrow Transplantation · 2010 · 37 citations · open access
Allogeneic Stem Cell Transplantation Using Myeloablative and Reduced-Intensity Conditioning in Patients with Major Histocompatibility Complex Class II Deficiency
AbstractMajor histocompatibility complex class II (MHC II) deficiency is a rare combined immunodeficiency disease. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment. Between June 1994 and February 2007, 30 children with MHC II deficiency underwent a total of 33 HSCT procedures. Median age at HSCT was 27 months. The stem cell source was unmanipulated bone marrow from HLA-identical related donors in 26 patients, one HLA antigen-mismatched bone marrow in 3 patients, and unrelated umbilical cord blood in 1 patient. Conditioning was with one of 3 myeloablative regimens--regimen A (18 patients): busulfan (Bu), cyclophosphamide (Cy), and etoposide; regimen B (2 patients): Bu, Cy, and antithymocyte globulin (ATG); or regimen C (1 patient): CY and total body irradiation (TBI)--or with a reduced-intensity regimen (12 patients): fludarabine, melphalan, and ATG. The median CD34 cell dose was 8.3 x 10(6)/kg. Twenty patients experienced immune reconstitution and had sustained engraftment ranging from 9% to 100% for lymphoid lines and from 5% to 100% for myeloid lines that were significant to cure the disease. The overall disease-free survival rate was 66% and 76% after HLA-identical HSCT, with a median follow-up of 6.3 years, which is higher than previously reported. In HLA-identical transplant recipients, reliable donor stem cell engraftment and immune reconstitution were achieved through myeloablative or reduced-intensity conditioning. Further studies and long-term follow-up are needed to determine the appropriate conditioning regimen.
Allergologia et Immunopathologia · 2017 · 23 citations · open access
MHC class II deficiency: Report of a novel mutation and special review
AbstractThe MHC II deficiency is a rare autosomal recessive primary immunodeficiency syndrome with increased susceptibility to respiratory and gastrointestinal infections, failure to thrive and early mortality. This syndrome is caused by mutations in transcription regulators of the MHC II gene and results in development of blind lymphocytes due to the lack of indicatory MHC II molecules. Despite homogeneity of clinical manifestations of patients with MHC II deficiency, the genetic defects underlying this disease are heterogeneous. Herein, we report an Iranian patient with MHC II deficiency harbouring a novel mutation in RFXANK and novel misleading clinical features. He had ataxic gait and dysarthria from 30 months of age. Epidemiology, clinical and immunological features, therapeutic options and prognosis of patients with MHC II are reviewed in this paper.
New England Journal of Medicine · 1995 · 19 citations
MHC Class II Regulation — Lessons from a Disease
AbstractElucidating the molecular and genetic basis of a hereditary disease often has implications that go beyond the understanding of the disease itself and that may concern important biologic processes. When it was shown that a form of primary immunodeficiency, major histocompatibility complex (MHC) class II deficiency (also referred to as the bare lymphocyte syndrome), was in fact a disease of gene regulation involving trans-acting regulatory factors,1 there was hope that elucidating the genetic basis of that rare disease might lead to the identification of the essential regulators of MHC class II gene expression. MHC class II genes, originally described . . .
GvHD scores after TBI (10 Gy) and BMT across different MHC disparities.
Abstract<p>(A) After BMT (with T-cell depletion) complete MHC or isolated MHC class II mismatch led to significantly higher GvHD scores over the course of time. (B) After BMT without T-cell depletion and additional donor lymph node cell injection a further increase of GvHD scores was observed in case of isolated mismatch of MHC class II as opposed to mismatch of MHC class I.</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.
