Junior Group Leader INSERM ATIP-Avenir, TaRGet – Translational Research in Gene Therapy, INSERM UMR 1089, IRS 2 Nantes Biotech – Nantes Université, FRANCE
Tuesday, 25 October 2022 | 12:00 noon – ICGEB Trieste, ITALY
Skeletal muscle organoids derived from pluripotent stem cells as a new model for preclinical gene therapy
Host: S. Zacchigna
Gene therapy is awaited with tremendous hope by patients suffering from neuromuscular disorders and their families. Zolgensma® has been approved in 2020 by regulatory agencies for young children with spinal muscular atrophy, and other recombinant adeno-associated virus (rAAV) vectors are being tested in patients with Duchenne muscular dystrophy (DMD) or X-linked myotubular myopathy (XLMTM). Although undoubtful clinical improvements have been obtained in phase I/II trials, they do not compare with the near complete disease correction observed in animal models. In a significant number of patients, the rAAV injection even led to serious adverse events that were never anticipated in preclinical studies, sometimes with a fatal issue. In this context, our lab is developing a disruptive in vitro platform for preclinical muscle gene therapy, with an improved capacity to predict treatment safety and efficacy. For this purpose, we are using human induced pluripotent stem cells (hiPSCs) and hydrogels to bioengineer miniaturized skeletal muscle organoids from healthy individuals and patients with DMD. Our activity is then divided in three major topics of interest: 1) we are using single-cell RNA-sequencing, reconstruction of developmental trajectories and predictions of gene regulatory networks to analyze myogenic differentiation and identify early DMD disease phenotypes that can hardly be described with in vivo experimentation; 2) we are carefully describing the structure and function of DMD organoids after myogenic differentiation and maturation, to identify the adult disease phenotypes that can be reproduced in hiPSCs-derived myotubes; 3) eventually, we are studying the ability of skeletal muscle organoids to be transduced with rAAV vectors of several serotypes, to optimize an in vitro gene therapy protocol. Altogether, these projects will help the development of a high-throughput preclinical testing platform for DMD and other skeletal muscle diseases, that will provide an alternative to animal experimentation for specific phases of drug development.
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