The application of established drug compounds to novel therapeutic indications, known as drug repositioning, offers several advantages over traditional drug development, including reduced development costs and shorter paths to approval. Recent approaches to drug repositioning employ high-throughput experimental approaches to assess a compound’s potential therapeutic qualities. Here we present a systematic computational approach to predict novel therapeutic indications based on comprehensive testing of molecular signatures in drug-disease pairs. We integrated gene expression measurements from 100 diseases and gene expression measurements on 164 drug compounds yielding predicted therapeutic potentials for these drugs. We demonstrate the ability to recover many known drug and disease relationships using computationally derived therapeutic potentials, and also predict many new indications for these drugs. We experimentally validated a prediction for the anti-ulcer drug cimetidine as a candidate therapeutic in the treatment of lung adenocarcinoma, and demonstrate both in vitro and in vivo using mouse xenograft models. This novel computational method provides a novel and systematic approach to reposition established drugs to treat a wide range of human diseases.

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. In this study, we applied a computational approach to discover novel drug therapies for IBD in silico using publicly available molecular data measuring 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 known to treat IBD, and topiramate, an anticonvulsant drug not previously described to demonstrate efficacy for IBD or any related disorders of inflammation or the gastrointestinal tract. We experimentally validated our topiramate prediction in vivo using a trinitrobenzenesulfonic acid (TNBS) induced rodent model of IBD. The experimental results demonstrate that oral administration of topiramate is able to significantly reduce gross pathological signs and microscopic damage in primary affected colon tissue in a TNBS-induced rodent model of IBD. These finding suggest that topiramate might serve as a novel therapeutic option for IBD in humans, and support the use of public molecular data and computational approaches to discover novel therapeutic options for IBD.

The functions of the proteins encoded by the Bardet-Biedl syndrome (BBS) genes are unknown. Mutations in these genes lead to the pleiotropic human disorder BBS, which is characterized by obesity, retinopathy, polydactyly, renal and cardiac malformations, learning disabilities, and hypogenitalism. Secondary features include diabetes mellitus and hypertension. Recently, it has been suggested that the BBS phenotypes are the result of a lack of cilia formation or function. In this study, we show that mice lacking the Bbs4 protein have major components of the human phenotype, including obesity and retinal degeneration. We show that Bbs4-null mice develop both motile and primary cilia, demonstrating that Bbs4 is not required for global cilia formation. Interestingly, male Bbs4-null mice do not form spermatozoa flagella, and BBS4 retinopathy involves apoptotic death of photoreceptors, the primary ciliated cells of the retina. These mutation data demonstrate a connection between the function of a BBS protein and cilia. To further evaluate an association between cilia and BBS, we performed homology comparisons of BBS proteins in model organisms and find that BBS proteins are specifically conserved in ciliated organisms.B ardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder with linkage to eight loci. Six BBS genes (BBS1, BBS2, BBS4, BBS6, BBS7, and BBS8) have been identified (1-7). With the exception of BBS6, which has similarity to type II chaperonins (8), BBS proteins do not show extensive homology with proteins of known function. BBS4 and BBS8 contain tetratricopeptide repeat domains, and a region of BBS8 shows similarity to the prokaryotic pilF domain. Based on the observations that BBS8 localizes to the basal body of ciliated cells and expression of the Caenorhabditis elegans orthologues of several BBS proteins are limited to ciliated cells, it has been hypothesized that BBS is the result of a defect in cilia assembly or function (7). We previously used positional cloning to identify the human BBS4 gene (3). To help elucidate the function of the BBS proteins, we have now targeted the Bbs4 gene in mice. Bbs4 Ϫ/Ϫ mice recapitulate aspects of the human phenotype: they become obese, fail to reproduce, and display retinal degeneration. We show the presence of both motile and primary cilia in these mice, demonstrating that Bbs4 deficiency does not prevent global ciliogenesis. Interestingly, male knockout mice have a complete lack of flagella, demonstrating that the Bbs4 protein is necessary for flagella formation during spermatogenesis. Furthermore, Bbs4-null mice undergo retinal degeneration due principally to photoreceptor cell loss associated with outer segment attenuation, suggesting a role for BBS proteins in maintenance of sensory cilia. These data demonstrate a role for BBS proteins in facets of cilia function. Materials and MethodsConstruction of the Bbs4 Gene Targeting Vector. BLAST analysis of the Celera mouse fragment database with the human BBS4 cDNA sequence identified sequences corresponding to...