title: Computational repositioning of the anticonvulsant topiramate for inflammatory bowel disease.
abstract: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract for which there are few safe and effective therapeutic options for long-term treatment and disease maintenance. Here, we applied a computational approach to discover new drug therapies for IBD in silico, using publicly available molecular data reporting gene expression in IBD samples and 164 small-molecule drug compounds. Among the top compounds predicted to be therapeutic for IBD by our approach were prednisolone, a corticosteroid used to treat IBD, and topiramate, an anticonvulsant drug not previously described to have efficacy for IBD or any related disorders of inflammation or the gastrointestinal tract. Using a trinitrobenzenesulfonic acid (TNBS)-induced rodent model of IBD, we experimentally validated our topiramate prediction in vivo. Oral administration of topiramate significantly reduced gross pathological signs and microscopic damage in primary affected colon tissue in the TNBS-induced rodent model of IBD. These findings suggest that topiramate might serve as a therapeutic option for IBD in humans and support the use of public molecular data and computational approaches to discover new therapeutic options for disease.
authors.affiliation: Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, 251 Campus Drive, Stanford, CA 94305-5415, USA.
authors.forename: Joel T
authors.initials: JT
authors.lastname: Dudley
authors.forename: Marina
authors.initials: M
authors.lastname: Sirota
authors.forename: Mohan
authors.initials: M
authors.lastname: Shenoy
authors.forename: Reetesh K
authors.initials: RK
authors.lastname: Pai
authors.forename: Silke
authors.initials: S
authors.lastname: Roedder
authors.forename: Annie P
authors.initials: AP
authors.lastname: Chiang
authors.forename: Alex A
authors.initials: AA
authors.lastname: Morgan
authors.forename: Minnie M
authors.initials: MM
authors.lastname: Sarwal
authors.forename: Pankaj Jay
authors.initials: PJ
authors.lastname: Pasricha
authors.forename: Atul J
authors.initials: AJ
authors.lastname: Butte
mesh_terms: D000927:Anticonvulsants / Q000627:therapeutic use*; D019295:Computational Biology / Q000379:methods*; D005632:Fructose / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077236:Topiramate
chemical_list: D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose