DeCure's autonomous Immuno AI scientist is researching a drug-repurposing hypothesis for inflammatory bowel disease 25 — 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 moduleInflammatory bowel disease 25 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 inflammatory bowel disease 25 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 10 receptor subunit beta (IL10RB) — IL10RB 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3LQM · 2.14 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
A genome-wide association study published in 2006 found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) conferred strong protection against Crohn's disease, and additional noncoding IL23R variants were independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. A 2007 review noted that genome-wide association studies had also strongly implicated the ATG16L1 (autophagy-related 16-like 1) gene, and that these findings promised to change fundamental understanding of IBD pathophysiology.
A 2010 review reported that interleukin 23 (IL-23) had been shown to induce colitis through its actions on innate immune cells, not only through enhancing the response of pathogenic IL-17-producing helper T cells. In mice lacking all lymphocytes of the adaptive immune system (Rag1 or Rag2 deficient), innate lymphocytes were sufficient to trigger inflammatory bowel disease. In the Helicobacter hepaticus model, neutralization of IL-23 ameliorated disease, and colitis development correlated with IL-23-dependent production of IL-17 and IFN-γ; blockade of either cytokine significantly reduced intestinal pathology. In the CD40 colitis model, blockade of IFN-γ significantly ameliorated disease, whereas blockade of IL-17 did not. The colitogenic cells in the H. hepaticus model coexpressed RORγt, CD127, CD90, CCR6, CD25 and Sca1, but did not express NKRs or high levels of CD117, markers reminiscent of lymphoid tissue inducer (LTi)-like cells. CD40-induced colitis development was abolished in Rag-deficient mice genetically lacking RORγt.
A 2005 review summarised earlier genetic discoveries including variants in CARD15, DLG5, SLC22A4 and SLC22A5 genes associated with increased risk of IBD or specifically Crohn's disease. A 2008 study tested UR-1505, a salicylate derivative that selectively down-regulates T-cell activation, in two protocols of dextran sodium sulfate (DSS) rat colitis: acute initial colitis (5% DSS for 5 days) and established colitis (2% DSS for 10 days after acute induction). UR-1505 did not exert a significant intestinal anti-inflammatory effect in ameliorating the initial steps of intestinal inflammation, but had a beneficial effect on ongoing inflammation. A 2022 review stated that conventional therapies for ulcerative colitis and Crohn's disease are inadequate and associated with several systemic side effects due to lack of localisation of active moiety at the inflamed site, and that colonic drug targeting is a novel area of research intended to ensure direct treatment at the disease site, lower dosing and fewer systemic side effects.
What is still missing is the translation of these genetic and immunological insights into reliably effective therapies for patients. The IL-23 pathway has been prioritised as a therapeutic target, but the 2022 review notes that conventional therapies remain inadequate. The UR-1505 compound showed benefit only in established colitis in rats, not in acute initial colitis, and has not been reported in human trials. No large, randomised, placebo-controlled trials have been published for any drug specifically targeting the innate lymphocyte subsets described in the 2010 review. Patient stratification by IL23R genotype or by the presence of particular innate lymphoid cell populations has not been tested in clinical trials. Funding for such trials and for the development of colonic drug delivery systems that achieve localisation without systemic side effects remains limited.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Science · 2006 · 3007 citations · open access
A Genome-Wide Association Study Identifies <i>IL23R</i> as an Inflammatory Bowel Disease Gene
AbstractThe inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.
The American Journal of Gastroenterology · 2007 · 86 citations · open access
The Genetics of Inflammatory Bowel Disease
AbstractGreat progress in the understanding of the molecular genetics of inflammatory bowel disease (IBD) has been made over the last 10 years. Strong epidemiological evidence, based initially on concordance data in twin/family studies, led to the application of genome-wide linkage analysis involving multiply affected families and the identification of a number of susceptibility loci. Further characterization of the IBD1 locus on chromosome 16 led to the discovery of the NOD2/CARD15 gene as the first susceptibility gene in Crohn's disease for 2001. This landmark finding has led to a redirection of basic research in IBD with interest focused principally on regulation of the innate immune response and mucosal barrier function. Within the last year, the use of genome-wide association studies has provided new insights into primary pathogenetic mechanisms; several new genes such as the Interleukin-23 receptor (IL23R) and ATG16L1 (autophagy-related 16-like 1) genes are strongly implicated. Overall, these studies promise to change our fundamental understanding of IBD pathophysiology and to have implications for clinical practice.
UR-1505, a salicylate able to selectively block T-cell activation, shows intestinal anti-inflammatory activity in the chronic phase of the DSS model of rat colitis
AbstractBACKGROUND: UR-1505 is a novel salicylate derivative compound that has been demonstrated to selectively down-regulate T-cell activation. The aim of the present study was to elucidate the mechanisms involved in the intestinal anti-inflammatory effects of UR-1505 in 2 protocols of a dextran sodium sulfate (DSS) model of rat colitis: acute and established colitis. METHODS: The first protocol consisted of incorporating DSS into the drinking water at a concentration of 5% (w/v) for 5 days (acute initial colitis). In the second protocol, once the acute colitis had been induced, the concentration of DSS was reduced to 2% (w/v) and maintained for 10 days (established colitis). RESULTS: The results obtained demonstrated that although UR-1505 did not exert a significant intestinal anti-inflammatory effect in ameliorating the initial steps of the intestinal inflammation induced by DSS, it had a beneficial effect on ongoing inflammation, most probably through inhibiting activation of T lymphocytes, thus avoiding perpetuation of the inflammatory process. CONCLUSIONS: These results suggest that this compound is a good candidate for inducing remission or maintaining therapies in human inflammatory bowel disease (IBD). Moreover, the different results obtained by UR-1505 in these 2 protocols of colitis induction (acute initial colitis versus established colitis) confirm the importance of selection and optimization of the experimental model to evaluate the drugs to be used in IBD therapy.
AbstractUntil very recently, interleukin 23 (IL-23) has been known to contribute to inflammatory bowel disease through its ability to enhance the response of pathogenic IL-17-producing helper T cells (Th17 cells). In a revelatory study by Powrie and colleagues,1 IL-23 has been shown to induce colitis through its actions on innate immune cells. Inflammatory bowel diseases (such as Crohn's disease, ulcerative colitis) are complex diseases driven by genetic and environmental factors leading to the initiation of an inappropriate immune response resulting in tissue destruction. Genome-wide association studies have identified the gene encoding for the IL-23 receptor (IL23R) as a susceptibility locus for Crohn's disease and ulcerative colitis.2 Data obtained from mouse models of inflammatory bowel diseases support the view that the cytokine IL-23 has a key role in inducing chronic and acute forms of inflammatory bowel diseases.3 A focus of most studies has been the role of IL-23 in enhancing or maintaining the response of Th17 cells, an effector T-cell population that is involved in various inflammatory and autoimmune disorders.4 Somewhat overshadowed is the role of IL-23 in regulating the function of innate lymphocytes, and their contribution to the pathogenesis of inflammatory bowel diseases is poorly defined. Now, Powrie and colleagues1 report that innate lymphocytes are sufficient to trigger inflammatory bowel disease in mice that lack all lymphocytes of the adaptive immune system (that is, T and B cells). These new data indicate that IL-23-triggered inflammation at mucosal sites is an evolutionary ancient program that precedes the development of adaptive immunity and puts the spotlight on innate lymphoid cells as new players in the pathogenesis of inflammatory bowel diseases. IL-23 is a member of the IL-12 cytokine family and its main mode of action is believed to be in peripheral inflamed tissues where it regulates the function of Th17 cells, a subset of effector CD4 T lymphocytes distinct from the previously recognized Th1 and Th2 cells. Th17 cells are characterized by the release of a defining array of cytokines, such as IL-17A (‘IL-17’), IL-17F, IL-21 and IL-22. Many of these regulate the function of nonhematopoietic cells and are potent inducers of chemokine production leading to the recruitment of proinflammatory cells.4 A role for IL-23 in driving inflammatory bowel diseases has been shown in various mouse models.3 Although pathology in many inflammatory diseases is driven by T cells, the role of innate immune cells in colitis is somewhat neglected despite the fact that IL-23 can regulate the function of innate lymphocytes.5,6 Available data indicated that colitis can develop in the absence of an adaptive immune system.7,8 For example, mice genetically lacking the recombination activating gene (Rag) 1 or 2 lack all B and T cells, yet develop chronic colitis (typhlocolitis) when infected with Helicobacter hepaticus.7 Neutralization of IL-23 ameliorated disease, and colitis development correlated with IL-23-dependent production of IL-17 and IFN-γ. Importantly, it is now shown that blockade of either cytokine significantly reduced intestinal pathology.1 A more general role of IL-23 in the onset of innate colitis was suggested by studies using systemic stimulation of myeloid cells with an agonistic CD40 antibody that led to acute IL-23-dependent colitis.8 In the CD40 colitis model, blockade of IFN-γ significantly ameliorated disease, whereas blockade of IL-17 did not.1 Collectively, these data indicate that innate immune cells are sufficient to induce colitis and that IL-23-induced IFN-γ and IL-17 might be important factors driving inflammatory bowel diseases in mice lacking an adaptive immune system. In those previous studies, the ‘colitogenic’ innate immune cell subset was not characterized. Mucosal innate lymphocytes are composed of at least four distinct subsets, natural killer (NK) cells, lymphoid tissue inducer (LTi)-like cells, NK receptor-expressing (NKR+) retinoic acid receptor-related orphan receptor (ROR) γt+ cells (also referred to as ‘NK-22’ or ‘NCR-22’ cells) and the recently identified fat-associated lymphoid clusters5,6,9,10,11,12,13 (Figure 1). Buonocore et al. provide the first evidence regarding the phenotype and lineage relationship of innate lymphocytes that might be important drivers of innate colitis. In the H. hepaticus model, an appreciable fraction of lymphocytes coproduced IL-17 and IFN-γ, which were required for disease. Phenotyping of these IL-17- and IFN-γ-producing colitogenic cells showed that they coexpressed RORγt, CD127 (IL-7Rα), CD90 (Thy1), chemokine (C–C motif) receptor 6 (CCR6), CD25 (IL-2Rα) and stem cell antigen 1 (Sca1), but did not express NKRs (such as NKp46) or high levels of CD117 (c-kit).1 These markers are reminiscent of LTi-like cells in the intestine of adult mice9. The development of LTi-like cells depends on the transcription factor RORγt and consequently, RORγt-deficient mice not only lack intestinal LTi-like cells but also NKR+ RORγt+ (NK-22) cells.6,9,11,12 To address the question whether a RORγt-dependent lymphocyte subset is involved in innate colitis, Powrie and colleagues turned to the IL-17-independent CD40 colitis model.8 CD40-induced colitis development was abolished in Rag-deficient mice genetically lacking RORγt but a RORγt-dependent, IFN-γ-producing lymphocyte subset was not identified (Figure 1). Collectively, the data obtained from these two innate colitis models suggest that RORγt-dependent or RORγt-expressing innate lymphocyte subsets are required for the development of innate colitis. Future research will be required to better define the colitogenic innate lymphocyte subset in each of these models. The cytokine profiles of the colitogenic cells in the two models were quite distinct, suggesting that different innate lymphocyte subsets might determine disease (Figure 1). For the H. hepaticus model, disease-inducing IL-17- and IFN-γ-producing cells phenotypically resembled intestinal LTi-like cells, but it remains unclear whether RORγt-deficient mice lack such cells or develop H. hepaticus colitis. In contrast, CD40-induced colitis did not require IL-17 but was driven by IFN-γ-producing lymphocytes.1 Although CD40 colitis was diminished in RORγt-deficient animals, the phenotype of the IFN-γ-producing cell remains unresolved (Figure 1). Whether colitogenic cells in these colitis models represent distinct functional states of LTi-like cells or different innate lymphocyte populations is unknown. An important question in this respect is whether IFN-γ-producing lymphocytes express RORγt as available data indicate that RORγt-expressing intestinal lymphocytes (LTi-like cells or NKR+RORγt+ cells) are producers of IL-17 and IL-22 but do not coproduce IFN-γ.6,11,12,14 In addition, IL-22-producing RORγt+ intestinal lymphocytes were found to promote epithelial homeostasis and protected against various other forms of colitis.6,11,12 Perhaps the different functional states of RORγt-expressing LTi-like cells might be explained by a certain degree of plasticity within the LTi cell lineage. Such plasticity has been recently described for RORγt-expressing Th17 cells that became IFN-γ producers once they were exposed to a cytokine environment that diminished RORγt expression.15 It was reasoned before that LTi-like cells may be uniquely positioned to support inflammatory diseases by organizing hyperplastic lymphoid clusters found in mouse models of colitis and in patients with inflammatory bowel diseases.16 Thus, the lack of CD40-triggered pathology in RORγt-deficient mice might reflect the lack of lymphoid structures as places for immune cell interaction and for priming of inappropriate inflammatory responses rather than the lack of a RORγt-dependent, IFN-γ-producing innate lymphocyte subset. These issues can only be addressed once mice allowing for the inducible ablation of RORγt-dependent cells become available. The new data now provide strong evidence that innate lymphocytes are sufficient to trigger and maintain chronic inflammatory disorders and that RORγt-expressing innate lymphocytes might be important drivers of inflammatory bowel diseases. Thus, IL-23-induced production of IFN-γ and/or IL-17 might represent an ancient inflammatory response program that might be further shaped by genetic and environmental factors, particularly by the commensal microflora. It is an interesting aspect of these and other recent data that the diversity of innate lymphocytes is much broader than previously appreciated. For a long time, NK cells were the lone representatives of the innate lymphocyte population, now LTi-like cells, NKR+RORγt+ (‘NK-22’) cells and fat-associated lymphoid clusters have come into focus6,13,14,16. An important area of future research will be to further explore their lineage relationships, functional properties and the transcriptional or developmental programs driving the differentiation of these innate lymphocyte subsets. It is striking that the functional profiles of innate lymphocytes accumulating at mucosal surfaces resemble those of the different T-cell subsets (Figure 1). This remarkable conservation of functional programs between adaptive and innate lymphocytes of the intestinal mucosa might reflect environmental challenges predating the emergence of adaptive immunity. Phenotype, function and developmental programs of innate lymphocyte subsets. The diagram depicts phenotype, RORγt expression and function of the two colitogenic subsets described by Buonocore et al.1 in the context of the previously characterized innate lymphocyte populations. Lymphocyte development is determined by the regulated expression of lineage-defining transcription factors (top). NK cell development is regulated by the transcription factor E4BP4 (NFIL3), whereas LTi cell fate is determined by RORγt. The transcriptional program of FALCs is currently unknown.
Expert Review of Clinical Immunology · 2005 · 2 citations
Genetic dissection of inflammatory bowel disease: unravelling etiology and improving diagnostics
AbstractOver the past 10 years, remarkable advances in the mapping and identification of genes involved in susceptibility to inflammatory bowel disease have been witnessed. Most notable among these advances has been the discovery of variants in the CARD15, DLG5, SLC22A4 and SLC22A5 genes, which are associated with increased risk of inflammatory bowel disease or specifically Crohn's disease. These discoveries have provided critical new insights into the molecular pathophysiology of inflammatory bowel disease and the pathways wherein genetic and environmental factors such as enteric bacterial flora may interact to trigger immune dysregulation and intestinal inflammation. This review will outline the discovery of these inflammatory bowel disease-related genes, describe future prospects for further inflammatory bowel disease gene identification, and consider the impact of a genetic understanding of inflammatory bowel disease on future clinical practice.
Saudi Journal of Medical and Pharmaceutical Sciences · 2022 · 1 citations · open access
Management of Inflammatory Bowel Diseases: A Review
AbstractInflammatory bowel diseases (IBD) are Ulcerative colitis (UC) and Crohn‘s disease (CD). Conventional therapies are inadequate and are associated with several systemic side effects due to lack to localization of active moiety at the inflamed site. Colonic drug targeting is a novel potentially active area of research intended and focused on drug delivery for treating localized disease. Targeted drug delivery to the colon would ensure direct treatment at the disease site, lower dosing and fewer systemic side effects.
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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