Project Objective and Overview: For neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), which are multifactorial in pathophysiology, the current preclinical drug screening tool capable of measuring only a few markers associated with ALS is not sufficient. Hence, a flexible in-vitro system based on human induced pluripotent stem cells capable of modeling complex ALS parameters is needed. We propose a completely novel preclinical model of human motor nerve tissue, "nerve-on-a-chip," that provides a 3D biomimetic system and enables assessments and measurements of ultrastructural neuromorphology as well as neurophysiological parameters.

Impact: A 3D system comprised of neuronal stem cells and specialized brain cells is expected to hold a significantly superior capability of predicting the mechanism of clinical nerve pathology as compared to conventional systems. In this proposal, several aims will be accomplished. First, a construct will be micro-engineered using induced pluripotent stem cells. Next, the constructs will be used to compare physiological changes between healthy neurons and mutated neurons. This will demonstrate the ability of the 3D model to serve as a feasible model in studying healthy versus mutated nerve cells. Finally, after demonstrating the ability to microengineer functional human motor nerves with and without a mutation, we will administer the FDA-approved drug Riluzole and five more compounds that have shown intervention in pathways associated with ALS. We hypothesize that acute administration of each drug will induce neuroprotection that may be detected using the model.

Market Opportunity: Completion of the aims will strongly support the feasibility of developing a useful nerve-on-a-chip model system. We have already established relationships with pharmaceutical companies who have expressed enthusiasm for this approach and a strong interest in partnering with us to utilize the model once it has been validated. Thus, the model is poised for translation as soon as its feasibility can be demonstrated. Hence, the end customers of the product will come mostly from the pharmaceutical industry, while ALS patients are expected to benefit from the widening of the ALS drug pipeline, which include only two approved drugs as of now.

Once on the market, the model, a medium-throughput, high-content microphysiological model of ALS, is expected to exert a significant impact on the drug discovery ALS field by enabling testing of large numbers of compounds or combinations of compounds for their impact on the neuronal environment in vitro, saving costly and time-consuming animal studies as well as improving the efficiency of clinical studies. Based on conversations with pharmaceutical industry stakeholders, the successful development of this model would cost 1/9 of the burden of animal testing and deliver results in weeks versus months, saving hundreds of thousands of dollars for a single exploratory preclinical test.

Clinical Interventions: The main goal of this project is to provide a commercial-ready, clinically relevant preclinical model to pharmaceutical companies developing therapeutics for ALS.