3D modelling of rare muscular diseases, a powerful platform for basic studies and drug validation

Muscular dystrophies, such as sarcoglycanopathies, are rare diseases currently incurable, resulting from genetic mutations causing a deficit of essential muscle proteins and compromising its functionality. For several years, we have been studying molecules, originally developed for cystic fibrosis (correctors) with excellent results, leading to the recovery of the missing protein in cells isolated from patients. To translate these results to humans we need verifying the effectiveness in complex organisms, typically animals. Unfortunately, in the case of sarcoglycanopathies, a major difficulty is represented by the fact that the model mice, carrying the same genetic mutations as the patients, do not develop the disease. To overcome this obstacle, the project proposes to generate artificial “model muscles”, using the cells donated by patients, modified in order to be usable for a long time (immortalized cells). For the generation of the artificial muscles we will apply two methods: 3D printing, using cells mixed with a gel as ink; the repopulation of the natural support of the muscle (the extracellular matrix) taken from mice and deprived of the original cells, preserving only the supporting proteins. The artificial muscles will be subjected to mechanical stimulation to reproduce the conditions of the moving muscle. Preliminary data show that both approaches generate constructs similar to human muscle reproducing some of the most significant aspects of the disease. This will allow the validation of potential drugs, defining doses and administration protocols. A similar approach could be applied in the study of therapies for other muscular dystrophies.