DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for leukocyte adhesion 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 moduleLeukocyte adhesion 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 leukocyte adhesion 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
integrin subunit beta 2 (ITGB2) — ITGB2 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 7USL · 2.7 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Leukocyte adhesion deficiency (LAD) is a rare inherited immunodeficiency in which leukocytes cannot migrate from the bloodstream to sites of infection. In a 2022 study of 67 Iranian patients (median age 18 months), the most common first presentations were omphalitis in 28.35% and delayed umbilical cord separation in 22.38%. Over the full course of disease, delayed umbilical cord separation occurred in 41.8% of patients, cellulitis in 40.3%, and omphalitis in 38.8%. Laboratory findings showed leukocytosis in 86.6% (neutrophil-dominant in 76.1%), anaemia in 77.6%, and thrombocytosis in 25.4%. CD18 was decreased in more than 90% of patients.
A 1997 case report described a patient with clinical features of mild LAD-1 — bacterial infections without pus, striking granulocytosis, no delayed-type hypersensitivity, no specific antibody generation, and normal in vitro T cell proliferation — yet with completely normal expression levels of CD11/CD18 proteins. Leukocyte activation did not produce CD11/CD18 high-avidity ligand binding, and in vitro chemotaxis, endothelial transmigration, and aggregation were almost absent. Beta1 and beta3 integrin functions were normal, but a bleeding tendency related to decreased beta3 activation later appeared. This was designated LAD-1/variant, the first documented case of nonfunctional CD11/CD18 molecules causing a combined immunodeficiency.
Earlier molecular analysis from 1988 established that LAD is due to heterogeneous mutations in the beta subunit common to the LFA-1, Mac-1, and p150,95 leukocyte adhesion glycoproteins. Infected necrotic lesions in these patients contain few leukocytes despite chronic leukocytosis. The disease is rare, but its study has clarified the biology of leukocyte adhesion proteins and the molecular mechanisms of immune response to skin infections.
Anti-adhesion therapy — blocking the leukocyte-endothelial adhesion cascade — has been tested in experimental animal models and clinical trials for inflammatory diseases. A 2005 review noted that many of these clinical trials yielded disappointing outcomes, and the authors argued that understanding the underlying mechanisms and timelines of leukocyte recruitment in each tissue and disease is crucial for developing more effective therapy. What remains missing is a therapy that can restore functional leukocyte adhesion in LAD patients without causing broad immunosuppression or bleeding complications; no such treatment has been tested in a controlled trial for LAD specifically, and patient stratification by residual integrin expression or function has not been prospectively evaluated.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Clinical Investigation · 1997 · 231 citations · open access
Leukocyte adhesion deficiency type 1 (LAD-1)/variant. A novel immunodeficiency syndrome characterized by dysfunctional beta2 integrins.
AbstractLeukocyte adhesion deficiency (LAD) is characterized by the inability of leukocytes, in particular neutrophilic granulocytes, to emigrate from the bloodstream towards sites of inflammation. Infectious foci are nonpurulent and may eventually become necrotic because of abnormal wound healing. LAD-1 is characterized by the absence of the beta2 integrins (CD11/CD18) on leukocytes. When expression is completely absent, patients often die within the first year. However, low levels of beta2 expression may result in a milder clinical picture of recurrent infection, which offers a better prognosis. In this paper, we describe the in vivo and in vitro findings on a patient with clinical features of a mild LAD-1 disorder, i.e., suffering from bacterial infections without apparent pus formation in the presence of a striking granulocytosis, showing no delayed-type hypersensitivity reaction upon skin testing, no specific antibody generation, but normal in vitro T cell proliferation responses after immunization. Expression levels of CD11/CD18 proteins were completely normal, but leukocyte activation did not result in CD11/ CD18 activation and high-avidity ligand-binding. In vitro chemotaxis and endothelial transmigration of the neutrophils as well as leukocyte aggregation responses were almost absent. On the other hand, beta1 and beta3 integrin-mediated adhesion functions were completely normal. During follow-up, a bleeding tendency related to decreased beta3 activation became clinically apparent, different from previously described cellular adhesion molecule variants. Therefore, this is the first well-documented case of a clinical combined immunodeficiency syndrome that results from nonfunctional CD11/CD18 molecules, and thus designated LAD-1/ variant.
Current Opinion in Hematology · 2007 · 79 citations
Genetics, biology and clinical management of myeloid cell primary immune deficiencies: chronic granulomatous disease and leukocyte adhesion deficiency
AbstractPURPOSE OF REVIEW: Chronic granulomatous disease and leukocyte adhesion deficiency are the major primary immune deficiencies affecting phagocytic blood cells. Major advances in clinical diagnosis and development of novel treatments for these disorders merit review. RECENT FINDINGS: Clinically beneficial gene therapy correction of X-linked chronic granulomatous disease in two adult patients was reported. Nonmyeloablative busulfan conditioning before administration of gene corrected autologous hematopoietic stem cells was likely an essential maneuver to achieve successful gene therapy. There is an increased association of autoimmune disorders with chronic granulomatous disease. Preimplantation genetic diagnosis of leukocyte adhesion deficiency-I led to the birth of a normal child. A canine model of leukocyte adhesion deficiency-I facilitated development of new nonmyeloablative hematopoietic stem cell transplant and gene therapy approaches to leukocyte adhesion deficiency. Nonmyeloablative transplantation may provide an effective, but less toxic approach for leukocyte adhesion deficiency in children. There have been advances in understanding the basis of leukocyte adhesion deficiency-II and III. SUMMARY: The most important subjects reviewed in this chapter include new advances in development of gene therapy for chronic granulomatous disease and leukocyte adhesion deficiency-I; transplantation for leukocyte adhesion deficiency-I; prenatal diagnosis of leukocyte adhesion deficiency-I; and association of autoimmune diseases with chronic granulomatous disease.
Therapeutic Intervention in Inflammatory Diseases: A Time and Place for Anti‐Adhesion Therapy
AbstractThe recruitment of leukocytes from the blood into tissue is central to the development and maintenance of the majority of inflammatory diseases. This multistep process requires a series of leukocyte-endothelial adhesive interactions, involving several families of adhesion molecules. Molecules that block these interactions have been targeted as potential therapeutic treatments for acute and chronic inflammatory diseases. However, many of the anti-adhesion therapy clinical trials have yielded disappointing outcomes. This review discusses some of the animal models that raise questions about the suitability of anti-adhesion therapy to treat certain inflammatory diseases. The authors suggest that it is crucial to understand the underlying mechanisms and time lines of leukocyte recruitment in each affected tissue and inflammatory disease to develop more effective anti-adhesion therapy.
Immunology and Genetics Journal · 2022 · 0 citations
Clinical Manifestations and Laboratory Findings in Patients with Leukocyte Adhesion Deficiency (LAD)
AbstractObjectives: Leukocyte Adhesion Deficiency (LAD) is a rare, inherited, immunodeficiency disease which is caused by defects in the leukocyte adhesion process. The migration of leukocytes to the blood vessel’s wall, needs multiple steps called adhesion cascade. In LAD, defects in rolling, integrin activation and firm adhesion of the leukocytes have been described. Methods: In this study, we selected 67 patients with the confirmed diagnosis of LADs, from Iranian immunodeficiency registry center. A demographic information of the clinical complications and laboratory data were obtained from all the patients to evaluate the clinical manifestations. Results: A total of 67 patients (38 male and 29 female), with a median age of 18 months old, were included in the present study. The first presentations were omphalitis in 28.35% of the cases, followed by delayed umbilical cord separation in 22.38% of the patients. The frequency of delayed umbilical cord separation was 41.8%, and was higher among other manifestations of our patients. Cellulitis and Omphalitis were observed in 40.3% and 38.8% of the patients, respectively. Regarding the laboratory findings, we found leukocytosis in 86.6 %( neutrophil dominant in 76.1%), and anemia in 77.6%, and thrombocytosis in 25.4% of the patients. Conclusion: We indicated in the present study that the most common clinical manifestations, were delayed umbilical cord separation and recurrent infection in Iranian patients with LAD disorders. In laboratory findings, we found leukocytosis in most of the patients. CD18 was decreased in more than 90 % of the patients.
Anti-adhesion therapy: Its current status and perspective.
AbstractIn acute inflammatory responses, a series of adhesive interactions occurs consecutively between circulating leukocytes and vascular endothelial cells of inflamed tissues. Recent studies have demonstrated that this leukocyte-endothelial adhesion cascade is mediated by a number of adhesion molecules and that the controlled inhibition of the adhesion cascade results in significant suppression of inflammatory and/or immune responses. Here we summarize our own attempts in such antiadhesion therapy in various experimental animal models and discuss its potential, limitation and future perspective.
Japanese Journal of Clinical Immunology · 1988 · 0 citations · open access
Molecular analysis of human leukocyte adhesion deficiency.
AbstractThe normal response of the immune system to infections of the skin or mucosal tissues requires the ability of peripheral blood leukocytes to mobilize to the site of infection. In a classical inflammatory reaction, neutrophils and monocytes migrate in response to chemotactic factors released at the infection site. However, until recently, the molecular mechanisms which enable leukocytes to migrate across blood vessels have been largely unknown. These mechanisms have been elucidated, in part, by the characterization of a recently defined disease called human leukocyte adhesion deficiency (LAD). Patients with this heritable disease suffer from severe recurrent bacterial and fungal infections of soft tissues, primarily skin and mucous membranes. Infected, necrotic lesions in these patients contain few leukocytes despite the observation that these patients have chronic leukocytosis. In the early 1980's, several laboratories demonstrated that this disease is due to a cell surface deficiency of the LFA-1, Mac-1, and p150, 95 family of leukocyte adhesion proteins. More recently we have shown that LAD is due to heterogenous mutations in the β subunit common to the all three of these leukocyte glycoproteins. Although LAD is a rare disease, the analysis of this disease has greatly increased our understanding of the biology of the leukocyte adhesion proteins and the molecular mechanisms involved in the immune response to infections of the skin.
AbstractAdhesion molecules play crucial roles in a variety of in vivo responses such as development of various tissues in embryos and also in the body defence mechanism in the postnatal period. Defects in adhesion molecules thus result in various pathological disorders. Recent investigation has identified a large number of novel adhesion molecules, particularly those involved in the extravasation of leukocytes including lymphocytes. However, there still appears to be a substantial number of unidentified adhesion molecules. In addition, signal transduction as well as regulatory mechanisms of adhesion molecules remain not fully explored. I will herein describe general characteristics of adhesion molecules and also discuss issues that need to be urgently resolved in the field of cell adhesion.
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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