Abstract

iPS Cells for Muscle Disorders: From Regenerative Medicine to Disease Modelling

Francesco Saverio Tedesco, Principal Research Associate, University College London

Mutations in the dystrophin gene cause Duchenne muscular dystrophy (DMD), which affects skeletal muscles, resulting in disability and premature death. Even though there is no cure, new treatments are currently under investigation. Among these, gene and cell therapy is particularly complex, as dystrophin Patient-specific stem/progenitor cells and large capacity vectors able to contain the entire dystrophin genetic locus, such as human artificial chromosomes (HACs), can be exploited to overcome these hurdles. We previously showed amelioration of the dystrophic phenotype of mice transplanted with murine, HAC-corrected muscle progenitors. However, translation of this strategy to the human setting requires cells able to withstand clonal expansion into clinically-relevant numbers to treat a dystrophic patient. Here I present two complementary strategies for the generation of HAC-corrected myogenic progenitors from DMD patients: one directly from skeletal muscle biopsies and the other from autologous iPS cells. In the case of adult muscle-derived cells, reversible immortalization using excisable telomerase and Bmi1 cDNAs allowed bypassing of replicative senescence and HAC transfer. When isolation of muscle-derived stem/progenitor cells proves challenging, fibroblasts can be reprogrammed to pluripotency and differentiated towards the specific myogenic lineage of interest, as we reported for Limb-Girdle 2D and Duchenne muscular dystrophies. We are now refining this iPS cell-based platform using non-integrating vectors and exploiting its potential for tissue engineering and drug development.