Disease Gallery – ALS

Amyotrophic Lateral Sclerosis (also known as Motor Neurone or Lou Gehrig’s Disease) is a complex, progressive neurodegenerative disease affecting 2-3 people per 100,000 and usually diagnosed between age 40-70. It is characterized by a peripheral neuropathy that migrates centrally, but disease causes, symptoms and progression appear to vary greatly between patients. There is no cure for the disease and there are only two approved therapies, which provide an average of 3 months’ extension to life.

We found 33 novel genes that were strongly associated with ALS and have selected 10 targets of significant interest for drug discovery screening. Within just 3 months of analyzing the ALS genotypes of more than 20,000 people, we are identifying potential new drugs for this debilitating disease. In a traditional drug discovery process, this usually takes 3-5 years.

Around 35 genes have previously been associated with ALS using GWAS and other approaches, but aside from a familial form, the disease is not strongly heritable. Existing targets that have been studied have not yet led to more effective therapies. We set out to identify ALL disease related genes to be able to prioritize and select new disease targets for drug repurposing and/or novel drug development programs.

We analyzed an ALS genotype only dataset supplied by MNDA and King’s College London, with 242,215 SNPs for each of 8,725 patients and 14,420 control subjects. Data were run through our automated precisionlife MARKERS analysis pipeline and the results were fully annotated using the precisionlife Annotator semantic knowledge graph. The most important disease associated SNPs and genes were ranked according to clinical relevance and heuristics including tissue expression, druggability, plausible mechanism of action hypothesis and available.

We found 33 novel high-scoring genes that were strongly associated with ALS risk in the dataset. These map well to known disease mechanisms and were validated by three independent KOLs, including at King’s College London and University of Sheffield. Further triage based on identifying known safe, selective, drug-like chemical starting points for 10 of the targets led to their selection for the current in vitro and in vivo testing in the Sheffield Institute for Translational Neuroscience (SITraN) facilities.

We are performing further lead optimization on our lead candidates in collaboration with our computational chemistry partners. Our hope is to demonstrate activity against a number of targets giving multiple new avenues of drug discovery into this devastating disease.