The Lieberam lab, in collaboration with the Lin group at QMUL, have developed the first human-relevant microphysiological model of neuromuscular circuits for Duchenne muscular dystrophy (DMD). Using optogenetics (light-dependent regulation of nerve cell activity), bioengineering techniques and pluripotent stem cells, the researchers have successfully controlled the activation of muscle fibre contraction by nerve cells in a culture dish.
DMD is caused by mutations is the dystrophin gene. It is a terminal disorder and the most common neuromuscular disorder in childhood. Patients with DMD experience progressive skeletal muscle weakness and wastage that leads to a loss of mobility and a reduced life expectancy. Although some of the symptoms of DMD can be ameliorated, there is no effective treatment or cure for the condition. Clinical progress for effective treatments and a cure for DMD has been hampered by a lack of human relevant microphysiological models.
In a new paper, published today in Science Advances, Paredes-Redondo et al. unveil their model for DMD using patient-derived and gene-corrected neuromuscular circuits in fabricated microdevices, that recapitulate key features of muscle-nerve connectivity in the human body. The authors identified abnormal gene expression in DMD myofibers, including key genes of the neuromuscular junction (NMJ), and showed that DMD compromises NMJ volumes and motor neuron-stimulated myofiber contraction.
In their paper, Paredes-Redondo et al. further established an assay for simultaneous drug screening for restoring NMJ defects and, unexpectedly, found that inhibition of TGFβ signalling using SB-431542, can restore motor function of DMD neuromuscular circuits, a finding beyond the known role of TGFβ signalling in myofiber homeostasis.
Dr Ivo Lieberam from the Centre for Developmental Neurobiology and the Centre for Stem Cells and Regenerative Medicine at King’s said:
”Our study provides evidence that Duchenne Muscular Dystrophy affects nerve-muscle connectivity, and we identify a candidate drug that can repair this damage in our experimental system. We gained this insight with a new stem-cell based model of human neuromuscular circuits, which may be closer to the disease in humans than experimental animals, and therefore more suitable for developing new therapies.”
This study presented the first model of its kind for DMD and in addition, holds promise for new targets and better therapies for people suffering from DMD and potentially other neuromuscular disorders.