<br/>An in vitro, human-based neuromuscular junction (NMJ) system capable of real-time measurement of muscle contraction would be advantageous to the drug discovery process for neuromuscular diseases including amyotrophic lateral sclerosis, myasthenia gravis and spinal muscular atrophy. Currently, there are few in vitro nerve-muscle systems composed of human cells, and none amenable to evaluating muscle force output induced by motoneuron stimulation through functional NMJs. Furthermore, no model systems, animal or human, have demonstrated the sensitivity necessary to generate dose response curves for the evaluation of pharmacological drug activity or toxicity. We have developed a serum-free, compartmentalized system containing human myotubes, and stem cell-derived motoneurons that supports the evaluation of neuromuscular junction physiology, and drug-induced pathology. The device, composed of two chambers linked by microtunnels to enable axonal outgrowth from the motoneuron chamber to the muscle, reproduces physiological NMJs and supports independent stimulation and evaluation of each component. Reduction in motoneuron-induced skeletal muscle output, measured by image subtraction video recordings, was observed in a dose-dependent manner following the application of bungarotoxin, botulinum toxin (BOTOX<sup>®</sup>) or curare. This human-based NMJ system, in combination with patient-derived iPSCs, establishes a platform for generating individualized models of neuromuscular diseases, a requirement for personalized medicine in this area.

Pharmacological evaluation of the neuromuscular junction in a human-based functional in vitro system

2019 Spring National Meeting

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