|From genetic findings to drug discovery: taking the first step|| |
|NA Patsopoulos1,2,3, JM Replogle1,2,3|
|1Brigham & Women's Hospital, Neurology, Boston, MA, United States, 2Harvard Medical School, Boston, MA, United States, 3Broad Institute, Cambridge, MA, United States|
|Background: Multiple Sclerosis (MS) is a demyelinating inflammatory disease with a strong genetic component. So far more than 100 genetic loci influencing MS susceptibility have been identified by genome-wide association studies (GWAS), with expectations to double this number in the near future. These findings have been integral to understanding the mechanisms and pathways of MS etiology, but an ultimate goal of the genetic era is to translate these findings into drug discoveries in order to improve patient outcomes.|
Objectives: To explore the potential of GWAS-identified genes in MS for drug targeting and to examine the overlap of these genes with targets of currently MS-approved treatments.
Methods: We used the most recently published large-scale genetic studies in MS to examine the associated genetic loci. Within these regions we identified genes genes putatively associated with MS based on proximity. Then we leveraged drug-gene interaction data (druggable genome; DGIdb ) to identify genes that either are targeted by a drug or have the potential to be. In a sensitivity analysis we expanded the list of tested genes by using information on direct protein-protein interactions (PPIs). Finally, we used the DrugBank v4.0 database to identify the gene targets of drugs currently approved for the management of MS.
Results: We identified 160 genes within 111 genome-wide published loci in MS. One fifth of these (n=33) had at least one known interaction with a drug or chemical compound, i.e. are druggable, with overall 138 distinct interactions. These included daclizumab, dinoprostone (prostaglandin E2), abatacept, and the general interferon family. Interestingly there were interactions with drugs that have MS as reported side effect, e.g. adalimumab. In the sensitivity analysis, we identified 793 genes with direct PPIs to MS-genes. Thirty percent (n=241) of these had at least one drug interaction, with ~2,000 interactions overall. In this level we identified MS-approved drugs (interferon betas and natalizumab), and several drugs under investigation for use in MS, e.g. masitinib, rituximab, memantine, alemtuzumab, etc.
Conclusions: We report the druggable potential of the GWAS-identified MS-genes via leveraging information on targets of drugs and chemical compounds. There is evidence that the currently approved or investigational MS drugs are directly or indirectly associated with GWAS-findings. We discuss how this information can be used in drug discovery and drug repositioning.
MD, PhD Nikolaos Patsopoulos , Brigham & Women's Hospital , Boston , US
Assigned in sessions:
11.09.2014, 17:00-17:45, Hot topic sessions, HT2, New routes of drug development (HT2.1-HT2.3), Auditorium