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.

Figure 1

Significant drug-disease scores for Crohn’s disease. The names of the drugs are placed along the bottom axis, and the vertical bars above the drug name indicate the computationally predicted therapeutic score for the drug based on comparison of the gene expression signature of the drug with the gene expression signature of Crohn’s disease. A positive score indicates that the drug exhibits an expression pattern that is synergistic with the disease, while a negative score indicates that the drug exhibits an expression pattern that is oppositional to the disease. Drugs are sorted from left-to-right starting with those predicted to be most efficacious for the disease. Green bars indicate drugs that are discussed in the text. The red triangle points towards the anticonvulsant drug topiramate, which was selected for experimental validation.

Figure 2

Gross clinical evaluation of IBD severity between treatment groups by percent of animals with diarrhea within each group. Both the topiramate treated group and the prednisolone treated group show reduced proportions of animals with diarrhea relative to the disease-induced group receiving only vehicle. (n=12 animals per group)

Figure 3

Pathological assessment of IBD severity between treatment groups. A) Clinical endoscopy captured from live animals on day 7 of the study. B) Gross pathology score. C) Pictomicrographs of H&E stained colon tissues showing microscopic damage to the mucosal and epithelial layers of the colon wall between treatment groups. D) Macroscopic damage score assessed from light microscopy of fixed colon tissues. Data graphs represent the mean and SEM estimated from three independent experiments. (n=12 rats per group) (* = P<0.05, ****=P<0.00005; Mann Whitney U test).

Figure 4

Evaluation and comparison of gene expression signatures for the drug compound topiramate and Crohn’s disease. A) Comparison of the Crohn’s disease signature (right) to the topiramate gene expression profile (left) showing a generally anti-correlated pattern, with genes at the top- and bottom-most ends of the expression pattern showing generally oppositional expression patterns. Genes that are up regulated are shown in green. Genes that are down regulated are shown in red. The pathways and functional groups significantly enriched (enrichment P-value < 0.05) in the top- and bottom 25% of genes are shown on the right hand side. B) qPCR results showing that gene transcripts for TRPV1 and IFI30 have oppositional gene expression levels in the disease condition (TNBS+vehicle) relative to the drug treated condition (TNBS+topiramate) in colon tissues collected from the animal validation study, which corroborates their expected oppositional relationship from initial comparison of the topiramate and Crohn’s expression signatures. (n=12 rats per group) (*=P<0.05, **=P<0.005; Mann Whitney U test; Error bars=SEM)