A017 A systems biology approach to gene network analysis and drug repositioning in Huntington’s disease

<h3>Background</h3> Despite extensive research, the complex pathophysiology of HD remains inadequately understood, and effective treatments are limited as there are only symptomatic treatments. Additionally, elevated complement component expression and aberrant complement system activation is one of the major interests in neurodegenerative diseases. <h3>Aims</h3> We aim to investigate the contribution of the complement system pathways to the dysregulated interactions of the Huntington’s disease pathology, and to identify disease-associated mechanisms and potential biomarkers for early diagnosis and possible therapeutic targets through system biology approaches at the transcriptomics level. <h3>Methods/Techniques</h3> Through the integration of publicly available gene expression data and constructing gene co-expression and protein-protein interaction networks, the players involved in complement system pathways related to the HD pathology were identified. <h3>Results/Outcome</h3> Weighted Gene Correlation Network Analysis (WGCNA) revealed two modules significantly correlated with HD pathology. The genes in these modules were intersected with complement system genes, resulting in the 33 upregulated genes. These genes were significantly enriched in complement system, peptidase activity, complement component C5a receptor activity, and peptidase regulator activity. The PPI network construction identified FN1, LYN, TNFAIP3, GNAI3, ANXA5, CTSS, SERPINA1, C5AR1, C3AR1, WAS, and C3 as potential biomarkers and therapeutic targets. Moreover, potential drug candidates that modulates the identified gene signatures with reversal effects were identified, and BRD-K96354014 was repositioned as possible treatment strategy that requires further clinical trials. <h3>Conclusions</h3> In this study, potential drug candidates modulating the identified gene signatures with reversal effects were identified, and BRD-K96354014 was repositioned as a possible treatment strategy.