Ferrari, Giulia; (2019) Developing new genomic integration-free gene and cell therapy strategies for muscular dystrophy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Duchenne muscular dystrophy (DMD) is caused by mutations on the Xlinked dystrophin gene and primarily affects skeletal muscles, resulting in disability and premature death. This thesis looks at different strategies to circumvent substantial obstacles in the development of therapies for this incurable disease. Here I hypothesise that the limited availability of large number of cells and the large size of the dystrophin gene (2.4Mb) can be tackled by combining human artificial chromosome (HAC)-based gene correction and induced pluripotent stem cell (iPSC)-mediated production of transplantable myogenic cells. However, another significant hurdle is posed by cell delivery, as skeletal muscle is the most abundant human tissue; therefore I also focused on developing a novel strategy to make the aforementioned DMD iPSC-derived myogenic population systemically deliverable. I hypothesised that cell fate modulators of native skeletal myoblasts could enhanced migratory properties also to human iPSCderived myogenic progenitors. I show that exposure to the Notch ligand DLL4 and PDGF-BB can induce the acquisition of some key properties such as a perivascular marker expression profile and an improved migration in vitro. Taken together these results lay the foundation for a small molecule-based strategy to allow systemic delivery of geneticallycorrected, genomic-integration-free, iPSC-derived myogenic cells for the autologous gene and cell therapy of DMD.

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