DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for DNA ligase IV 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 moduleDNA ligase IV 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 dna ligase iv 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
DNA ligase 4 (LIG4) — LIG4 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.
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RCSB Protein Data Bank · entry 9CQ3 · 2.8 Å · ligand 2'-deoxy-5'-O-[(R)-hydroxy{[(R)-hydroxy(phosphonooxy)phosphoryl]amino}phosphoryl]adenosine (DZ4). Experimental structure, not a prediction.
What the evidence adds up to
Two brothers with DNA ligase IV deficiency received allogeneic haematopoietic stem cell transplants from matched unrelated donors at 33 and 18 months of age. The older brother died 143 days after transplant from fatal side-effects. The younger brother, conditioned with a different regimen and given a T-cell-depleted graft, survived without severe side-effects and ten years later had a fully reconstituted immune system with maximum T-cell receptor diversity, though he still had microcephaly, dwarfism, and dystrophy. This single successful case used a mild conditioning regimen; no further patients have been reported with the same protocol.
Three unrelated patients described in a 2022 case series illustrate the wide clinical spectrum. One presented at age 5 with bone marrow failure, dysmorphic features, and T and B lymphopenia. A second presented at age 16 with recurrent infections, agammaglobulinaemia, and absent B cells. A third was referred for vitiligo, B-cell lymphopenia, and hypogammaglobulinaemia. Two of the three carried a homozygous R278H mutation in LIG4; the third had a compound heterozygous L19W/K635fs variant. No treatment outcomes were reported for these three patients.
A 1992 paper identified a protein inhibitor of DNA ligase I in HeLa cells, with a molecular mass of 55–75 kDa, that inhibited ligation by DNA ligase I but not by T4 DNA ligase or DNA ligase II. The inhibition was reversible by high-salt dissociation of the complex. This inhibitor has no known connection to DNA ligase IV deficiency, and no therapeutic application has been described.
What is missing is any prospective trial of haematopoietic stem cell transplantation in DNA ligase IV deficiency, any standardised conditioning regimen, any data on whether the successful outcome in one child can be replicated, and any stratification of patients by mutation type or clinical severity. The natural history of the disorder remains poorly defined, and no targeted therapy exists.
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 · 1994 · 46 citations
Normal V(D)J coding junction formation in DNA ligase I deficiency syndromes.
AbstractBloom syndrome and a clinically related syndrome represented by the cell line 46BR have been associated with reduction in DNA ligase I activity. In these syndromes, DNA ligase I deficiency severely impairs the development and function of the immune system. We undertook analysis of DNA ligase I-deficient cells to determine whether the observed immune deficiency is attributable to a perturbation in the process of V(D)J recombination. V(D)J recombination in Bloom syndrome cell lines and 46BR was examined by a transient transfection assay. No effect on the fidelity of coding and signal junction formation in DNA ligase I-deficient cells was observed. The frequency of V(D)J recombination in DNA ligase I-deficient cells was also examined using recombination substrates modified to function in human cells. Similar recombination frequencies were observed in normal and DNA ligase I-deficient cells, demonstrating that the efficiency of the V(D)J recombination process is unaffected by alterations in DNA ligase I activity. Rearranged immunoglobulin loci from Bloom syndrome cell lines and patient material were molecularly cloned by an inverse polymerase chain reaction strategy which should be applicable to a variety of human immunodeficiency syndromes and were indistinguishable from those found in normal bone marrow samples. Our data argue that the immune system defects associated with DNA ligase I deficiency do not result from perturbation of the V(D)J recombination pathway.
BMC Pediatrics · 2019 · 17 citations · open access
Allogeneic hematopoietic stem cell transplantation in two brothers with DNA ligase IV deficiency: a case report and review of the literature
AbstractBACKGROUND: DNA ligase IV deficiency is a rare autosomal recessive disorder caused by hypomorphic mutations in the DNA ligase IV (LIG4) gene. DNA ligase IV is an essential protein for the development of a healthy immune system as well as for the protection of genomic integrity. Apart from typical stigmata, patients with DNA ligase IV deficiency are characterized by progressive bone marrow failure and a predisposition to malignancy. To our knowledge this reported case is the first description of two brothers with ligase IV deficiency who are treated with different hematopoietic stem cell transplantation (HSCT) regimens resulting in vastly divergent outcomes. CASE PRESENTATION: The cases of two brothers suffering from severe recurrent infections and growth retardation are described. The laboratory findings showed pancytopenia with significant lymphopenia. The two boys were diagnosed with DNA ligase IV deficiency, associated with severe combined immunodeficiency (SCID). Both patients received HSCT from two different matched unrelated donors (MUD) at the age of 33 and 18 months. The older brother succumbed post-transplant due to fatal side-effects 143 days after allogeneic HSCT. The younger brother - conditioned with a different regimen - received a T cell depleted graft 4 months later. No severe side-effects occurred, neither post-transplant nor in the following years. Ten years after HSCT the patient is well off, living a normal life and attending a regular high school. His immune system is fully reconstituted, resulting in a maximum of T cell receptor (TCR) diversity, which is a prerequisite for immune competence. However, he still suffers from microcephaly, dwarfism and dystrophy. CONCLUSIONS: This case report gives an example of a successful HSCT as a treatment option in a genetic disorder such as ligase IV deficiency, using a rather mild conditioning regimen. Further studies are required to determine the viability and efficacy of this treatment option.
Proceedings of the National Academy of Sciences · 1992 · 14 citations · open access
Identification of a specific inhibitor for DNA ligase I in human cells.
AbstractA protein inhibitor for human DNA ligase I has recently been identified. It was copurified with a fraction of the enzymes from HeLa cells through several steps of chromatography. The inhibitor was first identified by the absence of ligation activity of the associated enzyme, while it retained the ability to form the ligase-[32P]AMP adducts. The inhibitor was eluted as a single peak at approximately 0.25-0.30 M NaCl from a Mono S column. It inhibited the ligation of both double-stranded and single-stranded breaks by purified DNA ligase I but not by T4 DNA ligase and DNA ligase II. Subsequent gel-filtration chromatography indicated that this inhibitor, with a molecular mass of 55-75 kDa, could form a complex with DNA ligase I and inhibited the DNA ligation activity. Rechromatography of the ligase I-inhibitor complex in high-salt conditions resulted in the dissociation of the complex and the restoration of enzyme activity, indicating that the physical interaction of inhibitor with DNA ligase I is one of the mechanisms of inhibition. These data indicate that this protein inhibitor for DNA ligase I may play a specific role in regulating DNA ligation during replication, repair, or recombination.
Frontiers in Immunology · 2022 · 5 citations · open access
Case Report: Wide Spectrum of Manifestations of Ligase IV Deficiency: Report of 3 Cases
AbstractDNA ligase IV deficiency is a rare autosomal recessive disorder associated with impaired DNA repair mechanisms. Most patients with DNA repair defects present with neurologic deficits, combined immunodeficiency, bone marrow failure, and/or hematologic neoplasia. We present 3 unrelated cases of ligase IV deficiency with different clinical presentations. Patient 1 presented at the age of 5 with bone marrow failure, dysmorphic features, and T and B lymphopenia. A compound heterozygous variant L19W/K635fs in the LIG4 gene was identified. Patient 2 presented at the age of 16 with recurrent infections. He had agammaglobulinemia and absent B cells. A homozygous R278H in the LIG4 gene was identified. Patient 3 was referred for vitiligo and B-cell lymphopenia (low class-switched B cells) and hypogammaglobulinemia. Homozygous R278H in LIG4 was also identified. In the last few years, the spectrum of clinical manifestations caused by ligase IV deficiency has widened, making it very difficult to establish an accurate clinical diagnosis. The use of NGS allows a proper diagnosis and provides a better prognosis and adequate family counseling.
AbstractHumans have three DNA ligases with distinct structural and biochemical features. Together, these enzymes are responsible for completing the majority of replication, repair, and recombination pathways. Deficiencies in the different enzymes cause different diseases and engineered cell lines lacking DNA ligases individually or in combination have challenged traditionally assigned roles of these enzymes. Quantitative mechanistic approaches with reconstituted enzymes and defined DNA breaks provide new insights into the substrate specificity and catalytic mechanisms of the different ligases that helps to define their normal biological roles and their compensatory roles when the other enzymes are compromised. These findings provide insight into the genomic instability of cancer cells and the immune deficiencies associated with defects in DNA ligases. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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.
