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ALS and neuro-muscular junctions

Amyotrophic Lateral Sclerosis

Neuro-muscular Junctions

Neuromuscular junction dismantling plays a crucial role in the onset of Amyotrophic Lateral Sclerosis (ALS). ALS is characterized by the degeneration and death of motor neurons leading to skeletal muscle denervation, atrophy and, most often, death of the patient within five years from diagnosis.
Successful co-culture with muscle fibers provide a functional human model of the neuromuscular junction, has exciting implications for drug discovery and R&D efforts to understand motor neuron disease.
By monitoring twitch and contraction activity, scientists now have a functional readout of the activity of the NMJ as a whole system. That insight means they can derive motor neurons from patient tissue and use them in the model to understand how functionality at the NMJ level is affected. They can then develop drugs to reverse or mitigate the effect of the disease.

An improved NMJ model for ALS

To date, many therapies for motor neuron diseases such as ALS have failed to make it out of the clinical trial phase. One reason for this could be the suitability of the experimental models used in the pre-clinical research and drug development phases.

In landmark work published in Scientific Reports Rimington et al. describe how they have succeeded in recreating the mature adult NMJ using Axol’s motor neuron progenitor cells (ax0078). The team hope their 3D human NMJ model will replace animal models and monolayer cellular models, improving the translation of therapies to the clinic.

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1. Rimington, R., Fleming, J., Capel, A., Wheeler, P., & Lewis, M. (2021). Bioengineered model of the human motor unit with physiologically functional neuromuscular junctions. Scientific Reports, 11(1). doi: 10.1038/s41598-021-91203-5
2. Osaki, T., Sivathanu, V., & Kamm, R. (2018). Engineered 3D vascular and neuronal networks in a microfluidic platform. Scientific Reports, 8(1). doi: 10.1038/s41598-018-23512-1
3. Kiernan, M., Vucic, S., Talbot, K., McDermott, C., Hardiman, O., & Shefner, J. et al. (2020). Improving clinical trial outcomes in amyotrophic lateral sclerosis. Nature Reviews Neurology, 17(2), 104-118. doi: 10.1038/s41582-020-00434-z
4. Petrov, D., Mansfield, C., Moussy, A., & Hermine, O. (2017). ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?. Frontiers In Aging Neuroscience, 9. doi: 10.3389/fnagi.2017.00068