ArticleGastroenterology2020
Drug Screen Identifies Leflunomide for Treatment of Inflammatory Bowel Disease Caused by TTC7A Deficiency.
Article in Gastroenterology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers, 2 of them syntheses that pooled it.
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Who cites it
45 citing papers in PubMed, 2 syntheses or guidelines pooled it, 65 citations in OpenAlex.
- A therapeutic atlas of monogenic inflammatory bowel disease.Journal of Crohn's & colitis · 2026Pooled it
- A Systematic Review of Monogenic Inflammatory Bowel Disease.Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association · 2022Pooled it
- TTC7A deficiency: A retrospective international study on treatment and outcomes from the Inborn Errors Working Party of EBMT.Journal of human immunity · 2026Article
- BIRC3 (Encoding cIAP2) Variants Result in Dysregulated RIPK1 Signaling Leading to Increased Epithelial Cell Death and Are Associated With Monogenic Crohn's Disease.Gastroenterology · 2026Article
- Integrating Human Intestinal Organoids into FDA's New Approach Methodologies for Drug Discovery.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Monogenic forms of inflammatory bowel disease: Genetic mechanisms, models, and clinical implications.Molecular medicine (Cambridge, Mass.) · 2026Review
- Immune-related actinopathies at the cross-road of immunodeficiency, autoimmunity and autoinflammation.Nature reviews. Immunology · 2026Review
- Video capsule endoscopy in very early onset inflammatory bowel disease: a multicenter retrospective study from the Chinese Pediatric VCE Study Group.Translational gastroenterology and hepatology · 2026Article
- Asian-Pacific perspectives on the management of very early-onset inflammatory bowel disease.Intestinal research · 2025Review
- The Genetic Architecture of Congenital Diarrhea and Enteropathy.The New England journal of medicine · 2025Article
- Inflammatory bowel disease risk gene C1ORF106 regulates actin dynamics in intestinal epithelial cells.bioRxiv : the preprint server for biology · 2025Article
- TTC7A Variants Results in Gastrointestinal Defects and Immunodeficiency Syndrome: Case Series and Literature Review.Clinical reviews in allergy & immunology · 2025Review
- Case Report: Prenatal diagnosis of gastrointestinal defects and immunodeficiency syndrome caused by compound heterozygous mutations in TTC7A gene.Frontiers in immunology · 2025Article
- Sphingosine-1-phosphate alleviates colitis by regulating macrophage polarization and PI3k-Akt signaling.Frontiers in immunology · 2025Article
- Cellular and molecular basis of proximal small intestine disorders.Nature reviews. Gastroenterology & hepatology · 2024Review
- Efficacy and Safety of Anti-Tumor Necrosis Factor Alpha in Very Early Onset Inflammatory Bowel Disease.Inflammatory bowel diseases · 2024Article
- Congenital Diarrhoeas and Enteropathies.Nutrients · 2024Review
- Breaking Down Barriers: Epithelial Contributors to Monogenic IBD Pathogenesis.Inflammatory bowel diseases · 2024Review
- A review on current advancement in zebrafish models to study chronic inflammatory diseases and their therapeutic targets.Heliyon · 2024Review
- Systematic review of phenotypes and genotypes of patients with gastrointestinal defects and immunodeficiency syndrome-1 (GIDID1) (related to TTC7A).Intractable & rare diseases research · 2024Review
Corrections and comments
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Authors and funding
16 authors at 6 institutions in 3 countries.
Funding
Abstract
BACKGROUND &
aimsMutations in the tetratricopeptide repeat domain 7A gene (TTC7A) cause intestinal epithelial and immune defects. Patients can become immune deficient and develop apoptotic enterocolitis, multiple intestinal atresia, and recurrent intestinal stenosis. The intestinal disease in patients with TTC7A deficiency is severe and untreatable, and it recurs despite resection or allogeneic hematopoietic stem cell transplant. We screened drugs for those that prevent apoptosis of in cells with TTC7A deficiency and tested their effects in an animal model of the disease.
methodsWe developed a high-throughput screen to identify compounds approved by the US Food and Drug Administration that reduce activity of caspases 3 and 7 in TTC7A-knockout (TTC7A-KO) HAP1 (human haploid) cells and reduce the susceptibility to apoptosis. We validated the effects of identified agents in HeLa cells that stably express TTC7A with point mutations found in patients. Signaling pathways in cells were analyzed by immunoblots. We tested the effects of identified agents in zebrafish with disruption of ttc7a, which develop intestinal defects, and colonoids derived from biopsy samples of patients with and without mutations in TTC7A. We performed real-time imaging of intestinal peristalsis in zebrafish and histologic analyses of intestinal tissues from patients and zebrafish. Colonoids were analyzed by immunofluorescence and for ion transport.
resultsTTC7A-KO HAP1 cells have abnormal morphology and undergo apoptosis, due to increased levels of active caspases 3 and 7. We identified drugs that increased cell viability; leflunomide (used to treat patients with inflammatory conditions) reduced caspase 3 and 7 activity in cells by 96%. TTC7A-KO cells contained cleaved caspase 3 and had reduced levels of phosphorylated AKT and X-linked inhibitor of apoptosis (XIAP); incubation of these cells with leflunomide increased levels of phosphorylated AKT and XIAP and reduced levels of cleaved caspase 3. Administration of leflunomide to ttc7a
conclusionsIn a drug screen, we identified leflunomide as an agent that reduces apoptosis and activates AKT signaling in TTC7A-KO cells. In zebrafish with disruption of ttc7a, leflunomide restores gut motility, reduces intestinal tract narrowing, and increases intestinal cell survival. This drug might be repurposed for treatment of TTC7A deficiency.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.