Neuromuscular junctions (NMJs) as therapeutic targets in MND

1) Making NMJs with human stem cells – a more clinically relevant model of MND.

Despite years of animal studies, no particularly effective treatments for motor neurone disease (MND) have been developed. Our goal is to study disease mechanisms, and screen treatments, in a more clinically-relevant disease model. We use human motor neurons from patient-derived induced pluripotent stem cells (iPSC-MNs) that develop disease features in culture.

Because MND is due to loss of MN contacts (neuromuscular junctions, NMJs) from muscle, blocking their loss is an important target for effective therapies. We use cutting-edge, microengineered culture chambers (‘microfluidics’) to allow iPSC-MNs to form NMJs on muscle cells in adjacent chambers. Each chamber can be independently monitored and controlled to study and manipulate NMJ pathology and disease progression. This system will also be used to screen potential therapeutics for maintaining NMJ function. If successful, this system will provide an important bridge between animal and clinical studies, more comprehensive studies of disease mechanisms, and a screen for novel therapeutic strategies.

2) Enhancing NMJ function to ameliorate symptoms in MND

Evidence suggest weakness in MND does to simply arise when motor neurons are lost, but occurs earlier as their NMJs lose effectiveness. Thus, supporting the function of these diseased NMJs is a potential target for improving patient strength and quality of life. Health NMJ effectiveness is carefully regulated in the body by signalling molecules released by MNs, muscle fibres and other cellular sources. We are investigating which signalling molecules are present, their role and how they might be targeted with therapeutic drugs to enhance NMJ function and muscle control, and thereby maximising patient quality of life.