Recent DNA/RNA sequencing and other multi-omics technologies have advanced our understanding of the biology and pathophysiology of Alzheimer’s disease. However, there is still a lack of disease modifying treatments for the condition. The researchers behind this study developed AlzGPS, a genome-wide positioning systems platform to help integrate the genome, transcriptome, proteome, and human interactome in the drug discovery and development process, to facilitate the development of disease modifying treatments for Alzheimer’s disease.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, which accounts for 60-80% of dementia cases. The condition causes cognitive decline and extensive neuropathological changes including deposition of extracellular amyloid plaques, intracellular neurofibrillary tangles and neuronal death. The number of patients suffering from AD is projected to reach 16 million by 2050 in the US alone. At present, there are no disease-modifying treatments for AD and no new drugs have been approved by the FDA since 2003.
Multi-omics data has increased our understanding of the pathophysiology of AD. For example, using single-cell RNA-seq, researchers were able to discover a novel microglia DAM, which is associated with AD that could offer new therapeutic targets. The large amount of multi-omics data and recent advances in network-based methodologies for drug repurposing present unprecedented opportunities for accelerating target identification for AD drug discovery. The core of network-based drug repurposing is that for a drug to be able to affect a disease, the targets must directly overlap or be in the immediate vicinity of the disease modules, which can be identified using high-throughput multi-omics data. On this principle, the researchers behind this study developed a comprehensive systems biology tool in the framework of network-based multi-omics analysis that can be used to inform Alzheimer’s patient care and therapeutic development.
AlzGPS (A Genome-wide Positioning Systems platform for Alzheimer’s Drug Discovery)
AlzGPS is a freely available database and tool for target identification and drug repositioning for AD. The AlzGPS database was built with large-scale diverse information including:
- Multi-omics (genomics, transcriptomics [bulk and single cell], proteomics and interactomics)
- Drug-target networks
- Literature-derived evidence
- AD clinical trials information
- Network proximity analysis
To develop AlzGPS, the researchers curated more than 100 AD multi-omics datasets, capturing DNA, RNA, protein and small molecule profiles underlying AD pathogenesis. Using that data, the researchers constructed endophenotype disease modules by incorporating multi-omics findings and human protein-protein interactome networks. AlzGPS also contains possible treatment information from around 3,000 FDA approved or investigational drugs for AD, which was made possible through the use of network proximity analyses. The researchers also curated almost 300 literature references for high-confidence drug candidates and included information from over 1,000 AD clinical trials noting drug’s mechanisms-of-action and primary drug targets. They then linked them to the AlzGPS integrated multi-omics view for targets and network analysis results for the drugs.
Overall, the online database can be used to provide network-based drug repositioning results and can be used to prioritise clinically relevant drug targets.
In summary, AlzGPS is the first comprehensive in silico tool for human genome-informed drug discovery for AD. The platform utilises multiple biological networks and omics data, and provides network-based drug repurposing results with the possibility for network visualisations. AlzGPS could be a powerful tool for prioritising biologically relevant targets and clinically relevant repurposed drug candidates for multi-omics-informed discovery in AD. Moreover, due to the nature of the data contained in the AlzGPS platform, the researchers state that it could be adapted and used for drug development for other neurodegenerative diseases.
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