Most candidate drugs currently fail later-stage clinical trials, largely due to poor prediction of efficacy on early target selection 1. Drug targets with genetic support are more likely to be therapeutically valid 2,3. The translational use of genome-scale data such as from genome-wide association studies (GWAS) for drug target discovery in complex diseases remains challenging 4-6. Here we show that integration of functional genomic and immune-related annotations together with knowledge of network connectivity maximizes the informativeness of genetics for target validation, defining the target prioritization landscape for 30 immune traits at the gene and pathway level. We demonstrate how our genetics-led drug target prioritization approach ("Priority index", Pi) successfully identifies current therapeutics, predicts activity in high-throughput cellular screens (including L1000, CRISPR, mutagenesis and patient-derived cell assays), enables prioritization of under-explored targets, and determines target-level trait relationships. Pi is an open access, scalable system accelerating early-stage drug target selection for immune-mediated disease. Fang et al.
Ankylosing spondylitis (AS) is a highly heritable chronic inflammatory arthritis characterized by osteoproliferation, fusion of affected joints and systemic manifestations. Many disease associations for AS have been reported through genome-wide association studies; however, identifying modulated genes and functional mechanism remains challenging. This review summarizes current genetic associations involving AS and describes strategic approaches for functional follow-up of disease-associated variants. Fine mapping using methods leveraging Bayesian approaches are outlined. Evidence highlighting the importance of context specificity for regulatory variants is reviewed, noting current evidence in AS for the relevant cell and tissue type to conduct such analyses. Technological advances for understanding the regulatory landscape within which functional variants may act are discussed using exemplars. Approaches include defining regulatory elements based on chromatin accessibility, effects of variants on genes at a distance through evidence of physical interactions (chromatin conformation capture), expression quantitative trait loci mapping and single-cell methodologies. Opportunities for mechanistic studies to investigate the function of specific variants, regulatory elements and genes enabled by genome editing using clustered regularly interspaced short palindromic repeats/Cas9 are also described. Further progress in our understanding of the genetics of AS through functional genomic and epigenomic approaches offers new opportunities to understand mechanism and develop innovative treatments.
Transcription activator-like effectors (TALEs), originating from the Xanthomonas genus of bacteria, bind to specific DNA sequences based on amino acid sequence in the repeat-variable diresidue (RVD) positions of the protein. By altering these RVDs, it has been shown that a TALE protein can be engineered to bind virtually any DNA sequence of interest. The possibility of multiplexing TALEs for the purposes of identifying specific DNA sequences has yet to be explored. Here, we demonstrate a system in which a TALE protein bound to a nitrocellulose strip has been utilized to capture purified DNA, which is then detected using the binding of a second distinct TALE protein conjugated to a protein tag that is then detected by a dot blot. This system provides a signal only when both TALEs bind to their respective sequences, further demonstrating the specificity of the TALE binding.
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