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Developing new genomic integration-free gene and cell therapy strategies for muscular dystrophy

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.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Developing new genomic integration-free gene and cell therapy strategies for muscular dystrophy
Event: UCL (University College London)
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10078330
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