Identifying ALS Therapeutics Through Multiplexed Drug Discovery Technologies

Amyotrophic lateral sclerosis (ALS) is a disease in which patients suffer continuous loss of motor neurons, leading to an inability to voluntarily move, speak, chew, or breathe. Despite billions of dollars in investment, decades of research, and more than 50 failed clinical trials over the past 20 years, current treatments are only able to slightly delay disease progression. The lack of effective treatments may be due to research groups using a single disease model in the early stages of drug development. Because the mechanism of ALS differs between patients, performing drug discovery within a single disease model may select for drugs that work only within the few lucky patients that have a genetic makeup similar to the disease model used for drug discovery. In this proposal, we describe a more comprehensive and efficient strategy for identifying potential drugs for ALS. Our approach is based on using a new drug discovery platform that will allow us to examine nearly a dozen different models of ALS simultaneously. By testing multiple disease models in parallel, we will be able to better identify therapeutics that have the potential to benefit multiple types of ALS patients. In addition, the new discovery platform is designed to provide much more information about each candidate drug up-front, including data on potency and safety, so the most promising compounds can be identified for further study. Moreover, by making our data freely available, we will create a foundational dataset upon which the larger scientific/ALS research community can build upon and pursue their own independent preclinical/clinical trials based on the unique compounds we identify. The described studies are the first step toward eventual clinical trials. For promising candidate drugs identified with our platform that are already approved for treatment of other human diseases, we can quickly proceed to testing in ALS animal models to see if they improve animal health. Drugs that show benefit to animals will then be taken into phase I/II clinical trials in collaboration with potential pharmaceutical partners and the Eleanor and Lou Gehrig ALS Center at Columbia University Medical Center. This process is anticipated to take 2-4 years from the end of our proposed studies, until the initiation of human clinical trials. Entirely novel compounds without previous use in humans will require additional study and optimization before they can be tested in human clinical trials, with a timeline of 4-6 years from the end of our outlined studies to human testing.