Patient Motor Neuron Assay System for ALS Drug Discovery

Project Summary Abstract Amyotrophic lateral sclerosis ALS also known as Lou Gehrig s disease is a devastating neurological disorder with patients typically surviving just three to five years after diagnosis Approximately Americans live with ALS and another are diagnosed each year ALS Association Despite identification of over candidate drugs from studies with model animals and immortalized human cell lines over the past two decades only a single FDA approved drug riluzole Rilutek is available to treat the disease increasing survival of patients by two to three months This sobering status highlights an urgent need of novel pharmaceutical therapies perhaps via a new drug discovery platform BrainXell Inc seeks to create a naturalistic in vitro screening platform to identify promising ALS drug leads for further development By generating induced pluripotent stem cells iPSCs from ALS patients we discovered that the iPSC derived motor neurons MN exhibit neurofilament NF aggregation followed by axonal degeneration and finally MN death reminiscent of the cardinal pathology seen in ALS patients We further found that a subunit of NF NF light chain NF L was decreased and if NF L level was restored NF aggregation and neurite degeneration were mitigated even in the presence of disease mutations Thus NF misregulation is a critical cause of NF aggregation and MN degeneration and hence a potential therapeutic target The company has recently engineered ALS patient iPSCs with a reporter gene nanoluciferase times more sensitive than the traditional luciferase fused to NF L to allow for a simple robust readout of NF L protein level It has recently developed a technology to generate large quantities of motor neurons billions in one batch from patient iPSCs making high throughput screening HTS possible This proposal will build upon these technologies and determine the feasibility of establishing an HTS platform for ALS drug discovery using patient MNs This effort likely represents the first ever patient cell based HTS platform It will provide an opportunity to screen compound libraries in a biological system that more closely resembles the disease as it exists in man Project Narrative BrainXell proposes to test the feasibility of using patient derived motor nerve cells to discover new drugs These drugs would be targeted at amyotrophic lateral sclerosis ALS also known as Lou Gehrig s disease a degenerative neurological disorder without an effective treatment