REPURPOSING DRUGS FOR HYPERCOAGULABLE CONDITIONS: A PRECISION MEDICINE APPROACH TO ADVANCE THERAPEUTIC DISCOVERY

Abstract

Background: Sickle Cell Disease (SCD) and related hypercoagulable conditions, particularly those associated with elevated von Willebrand factor (vWF) levels, pose significant health challenges globally, with a notable burden in Saudi Arabia. Despite known genetic factors influencing these conditions, effective treatment options remain limited. This dissertation aims to leverage genomic data and bioinformatic techniques to identify novel therapeutic targets and drug repurposing opportunities for SCD and vWF-linked hypercoagulability. Methods: This research comprises three interconnected studies. First, a case-control Genome-Wide Association Study (GWAS) was conducted comparing Saudi SCD patients with healthy controls. The second study utilized bioinformatic pipelines to analyze the druggability of the identified genes that characterize Saudi SCD patients. The interaction of these genes with the currently approved medications was estimated. The third study extended this approach to vWF-linked hypercoagulability, utilizing publicly available GWAS data. These analyses integrated data from various sources, including databases of drug-gene interaction and protein structures, to identify potential drug repurposing candidates and novel drug targets. Results: The initial GWAS identified numerous significant genetic variants characterizing SCD cases in the Saudi population. Building on these findings, the second study revealed several approved medications showing potential for repurposing in SCD. Notably, drugs such as simvastatin, allopurinol, and specific immunomodulators have emerged as promising candidates. The analysis also identified novel drug targets with high druggability scores, in particular, the olfactory receptor gene clusters. The third study, focusing on vWF-linked hypercoagulability, identified additional potential candidates, including nebivolol, pravastatin, riociguat, candesartan, and acetylcysteine. This study also revealed several novel, highly druggable targets implicated in key processes related to blood coagulation and vascular function, such as CLEC4M and SLC44A2. Conclusion: This research provides a comprehensive framework for drug repurposing and novel drug discovery in SCD and related hypercoagulable conditions. The findings underscore the potential of leveraging genetic data to identify targeted therapies, offering a pathway to more personalized and likely effective treatments. While promising, these computational predictions require further validation through conducting clinical studies to be translated into clinical practice.