A High-Throughput Phenotypic Screen for C9ORF72 ALS Therapeutics Using Patient-Specific Motor Neurons
Abstract
This proposal describes a collaboration between the University of Southern California and one of the world s leading pharmaceutical companies, Sanofi, to develop a cure for Lou Gehrig s disease, also called amyotrophic lateral sclerosis (ALS). We propose to utilize cutting-edge stem cell technology to identify a drug-like compounds that can keep nerve cells from alive in ALS patients. We hope that these compounds eventually can be tested in all types of ALS patients to treat this devastating disease. We have collected blood from ALS patients with a specific mutation, C9ORF72. This mutation is the most common cause of familial and sporadic ALS, accounting for more than 50% of cases in northern Europe and 5%-10% of cases worldwide. My group will also collect blood from patients with all types of ALS. A new stem cell technology we developed allows my lab to convert C9ORF72 ALS patient blood cells into the motor neurons that are affected in ALS patients. Previous studies by my group show that these patient motor neurons die faster than normal motor neurons and that they recapitulate the "disease in a dish." My group previously examined more than 800 chemicals and identified 4 that can keep the C9ORF72 ALS patient cells alive as long as normal cells. With this knowledge in mind, we want to expand our study to 40,000 chemicals from Sanofi, the world s fourth largest pharmaceutical company. We will test the lead compounds from the screen against a panel of different ALS patient cells. This is a new way to evaluate the efficacy of a new drug. Those that work in majority of ALS patients would be chosen as the top of the list. Since these 40,000 chemicals are the best understood of Sanofi s much larger collection of millions of chemicals, if a compound from this collection of 40,000 proves to prolong the survival time of most ALS patient motor neurons, Sanofi scientists will immediately understand what the compound does to the cell, thereby accelerating the process of moving the chemical into clinical trials. At the end of this 3-year study, we will have a few lead chemicals that are ready to be tested in an appropriate animal model of ALS. In another year or so, one of these lead chemicals will be selected to test in human clinical trials for ALS. The "disease in a dish" technology developed by my lab has proven to be very effective, and this is the first large-scale attempt to use this technology to find potential drugs. Most drug discovery efforts for ALS have failed so far, and the only Food and Drug Administration-approved drug on the market, Riluzole, only extends a patient s life for about a month. The new technology described here will likely overcome the problems encountered in the previous ALS drug discovery efforts and identify a true cure for ALS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510187
Entities
People
- Justin K Ichida
Organizations
- United States Army
- University of Southern California