Project R-17011

Development of human iPSC-derived neuromuscular junctions on a chip to study amyotrophic lateral sclerosis (ALS) (Research)

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder leading to progressive muscle weakness, dysarthria, dysphagia and respiratory muscle weakness. The average survival after disease onset is limited to 2 to 5 years. There is a high unmet medical need for this disease, as no effective therapies exist. In order to change this, model systems mimicking as closely as possible the disease process are crucial. The aim of our project is to create an improved human 'neuromuscular junction (NMJ)-on-a-chip' model. This is highly relevant to the disease as ALS is caused by a 'dying back' mechanism starting at the NMJs, connecting the motor neurons with the muscles. Therefore, we will differentiate human induced pluripotent stem cells (iPSCs) into different cell types (motor neurons, myotubes, astrocytes, microglia, Schwann cells) and investigate the effect of these cells. In addition, we will investigate the effect(s) of the factors secreted by dental pulp stem cells (DPSCs) and of disease-causing ALS mutations present in 10% of ALS patients (familialALS) on the generation and maintenance of the NMJs. We will combine the different iPSC-derived cell types with both stimulating and recording electrodes, enabling us to record the electrical activity of both the motor neurons and the myotubes, as well as with molecular sensors. Moreover, we aim to miniaturize the model and to automate the quantification of the establishment and degeneration of the NMJs. By doing so, we will generate a novel model which we will use to get insights into the molecular events leading to denervation of the NMJs, as well as to test new therapeutic strategies. As denervation is a common hallmark of many neuromuscular disorders as well as of sarcopenia, a successful human 'NMJ-on-a-chip' model will have a much broader application beyond ALS.

01 October 2026 - 30 September 2030