In the clinical development pipeline, 40-50% of drugs fail during Phase 1/Phase 2 of the programme due to sub-optimal drug efficacy (1). This is often attributed to the poor selection of a drug target that is not linked to the disease mechanism of the intended indication. To enhance the rate of success in developing a drug, it is critical to identify promising targets that have a proven relationship with the disease.
Genome-wide association studies (GWAS) is one of the most extensively used methods to identify causal genes of a disease or trait. Selecting a target that is supported by genetic evidence increases the success rate in the clinical development pipeline by four-fold in the pre-clinical stage, and by two-fold in clinical research (2).
Causaly uses the GWAS Catalog as one of its data sources to help you identify genetically-supported targets and validate gene-disease relationships. You can visit this page to learn how to find genetic evidence from the GWAS Catalog.
Finding genetic variants affecting ALS
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons in the brain and spinal cord, resulting in muscle weakness and wasting (3). There is currently no cure for ALS, but the surfacing of more than 20 genes and genetic risk factors associated with ALS has offered the opportunity to develop gene therapies targeting these mutations (3, 4).
Using Intelligent Search in Causaly, more than 8,000 articles related to ALS were screened to extract over 1,800 genes and proteins affecting ALS (link). You can explore this list of genes and proteins in the dendrogram view where the most extensively studied results are prioritized (Figure 1).
Figure 1. Dendrogram view of genes and proteins affecting ALS (top 20 results).
In Causaly we can easily narrow down to genetic evidence coming from the GWAS Catalog by applying a single filter (link). The updated list returns 35 genetic variants affecting ALS. The more well-known genetic risk factors C9orf72 and UNC13A are prioritized in the dendrogram, followed by CFAP410 and other genetically-supported targets (Figure 2).
Figure 2. Genetic variants affecting ALS from the GWAS Catalog (top 20 results).
A simple click on ‘CFAP410’ allows the inspection of the genetic association with ALS. On the sidebar, we find that missense mutations of CFAP410 are linked to ALS from snippets of three individual GWAS (Figure 3).
Figure 3. Missense variant of CFAP410 is linked to ALS.
Once a genetically-supported target has been identified, use Causaly to find evidence from the other data sources. Investigate the relationship between CFAP410 and ALS in Intelligent Search to find all the supporting evidence in the literature (link). The system discovers insights from other approaches such as bioinformatics and molecular modelling (Figure 4). In addition, you can click on ‘Multi-Hop’ to break the relationship and thereby investigate the indirect links in the target-disease relationship.
Figure 4. Literature insights supporting the relationship between CFAP410 and ALS.
Conclusion
In this use case study, Causaly screens over 8,000 documents to discover a list of genes and proteins affecting ALS. Within seconds, Causaly identifies 35 genetically-supported targets for ALS from the GWAS Catalog and enables target validation by providing additional insights in the field as well as the functionality to investigate the underlying mechanistic link in the target-disease relationship.
References
- Harrison R. K. (2016). Phase II and phase III failures: 2013-2015. Nature reviews. Drug discovery, 15(12), 817–818. https://doi.org/10.1038/nrd.2016.184
- Nelson, M. R., Tipney, H., Painter, J. L., Shen, J., Nicoletti, P., Shen, Y., Floratos, A., Sham, P. C., Li, M. J., Wang, J., Cardon, L. R., Whittaker, J. C., & Sanseau, P. (2015). The support of human genetic evidence for approved drug indications. Nature genetics, 47(8), 856–860. https://doi.org/10.1038/ng.3314
- Masrori, P., & Van Damme, P. (2020). Amyotrophic lateral sclerosis: a clinical review. European journal of neurology, 27(10), 1918–1929. https://doi.org/10.1111/ene.14393
- Amado, D. A., & Davidson, B. L. (2021). Gene therapy for ALS: A review. Molecular therapy : the journal of the American Society of Gene Therapy, 29(12), 3345–3358. https://doi.org/10.1016/j.ymthe.2021.04.008