Drug repurposing candidates for amyotrophic lateral sclerosis using common and rare genetic variants.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative condition for which novel disease modifying therapies are urgently needed. Given the increasing bottlenecks in drug discovery pipelines, repurposing existing drugs for ALS may represent a path to expedite translation and improve disease outcomes. However, ALS is a heterogeneous disease for which the aetiology remains poorly characterized, complicating efforts to effectively repurpose drugs. We propose that the polygenic architecture of ALS genetic liability, which ranges from ultra-rare, high-impact variation to common frequency loci of small-individual effect, could be leveraged to prioritize drug repurposing candidates which are more generalizable to the ALS clinical population. Here, we utilize common and rare frequency ALS genetic risk with a novel approach to uncover therapeutic classes that may be prospective repurposing opportunities in ALS. The common variant-led analyses integrated both positional-based and functional gene-based tests on SNP-genotype data from a genome-wide association study of ALS and implicated mitogen-activated protein kinase signalling related downregulation through B-Raf inhibitors as a prospective target for repurposing. The rare variant-led approaches leveraged rare variant burden testing of exonic variation on whole genome-sequencing data from a subset of the common variant genome-wide association study cohort and prioritized B-vitamin related candidates, such as cobalamin and niacin. Clinical characterization of these putative repurposing opportunities revealed genetic support to existing biology for which related compounds are actively proceeding through ALS clinical studies. Moreover, leveraging transcriptomic data from ALS derived cell lines carrying a selection of pathogenic variants in genes that cause familial forms of ALS (