PROJECT SUMMARY / ABSTRACT Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons in the spinal cord and brain. ALS causes muscle weakness and paralysis and eventually death. According to the ALS Association, every 90 minutes there is a new diagnosis of ALS, as well as an associated death. Nearly 5,000 people are diagnosed with ALS each year and at least 16,000 are living with the disease at any given time in USA alone. There are 3 FDA-approved drugs for ALS, however, the effectiveness of these drugs is limited. In this Phase 1 STTR project, we propose translational studies to evaluate the effects of a recently developed neuronal hyperexcitability suppression technique in ALS models. If successful, the implications of the current project are far-reaching changes in clinical practice for treating ALS using non-invasive hyperexcitability suppression. PathMaker Neurosystems Inc. is a clinical-stage neuromodulation company developing first-in- class devices for the treatment of serious neurological disorders based upon our pioneering multi-path DCS technology, which enables the non-invasive modulation of spinal circuits and motor neuron activity. Our objective for this Phase 1 STTR project is to conduct key translational studies that will be essential for advancing this hyperexcitability suppression technology towards human clinical trials as a safe and efficacious new treatment for ALS. The project consists of 3 Specific Aims: In Specific Aim 1, we will develop and deliver research-use multi-path DCS devices facilitating concurrent animal stimulations. In Specific Aim 2, we will expand on initial transgenic ALS mouse studies to further assess the effects of multi-path DCS on survival, motor function and excitability. In Specific Aim 3, we will conduct motor neuron counts to assess the effects of multi-path DCS on motor neuron survival. These Specific Aims will help generate a package of pre-clinical data that will provide a basis to move the technology into a human clinical feasibility study. As our company works to translate the groundbreaking academic studies that have identified a novel approach to the treatment of ALS based on neuronal hyperexcitability suppression, Phase 1 STTR support will advance this revolutionary treatment option to the brink of human clinical trials, and will pave the way for application of this technology to potentially other motor neuron diseases.