Basche, MDA; (2014) Gene therapy approaches to disease of the cornea and anterior chamber. Doctoral thesis , UCL (University College London).

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Abstract

The field of ocular gene therapy has become one of the most developed areas within the wider gene therapy field, however most work to date has focused upon the retina with the cornea, by comparison, having seen relatively little application of gene therapy. This thesis describes a program of work to further develop viral gene therapy approaches to the three cellular layers of the cornea, with particular emphasis upon the application of novel vector technologies and overcoming the various challenges presented by each layer. Gene therapy of the corneal endothelium has to date largely aimed to increase or maintain endothelial cell density to improve the quality of donor corneas for engraftment. Such a strategy however carries an inherent risk of oncogenesis and this study has therefore aimed to improve the safety profile of endothelial gene delivery methods. The transduction profile of various AAV serotypes within the corneal stroma was also investigated, and the most promising results applied in an augmentation gene therapy approach to prevent corneal neovascularisation. The selected methodology is shown to mediate high level transgene expression and, when delivering the antiangiogenic factor sFlt1, was highly effective in preventing haem (but not lymph) angiogenesis in a murine model of induced corneal neovascularisation. If long term gene delivery to the corneal epithelium is to be achieved it must be targeted to the limbal epithelial stem cells (LESCs) responsible for the continuous regeneration of the layer. This study has convincingly demonstrated gene delivery to these cells in vivo for the first time, with the methodology developed leading to a lasting transgene expression throughout the LESC daughter cell lineages that comprise the epithelium. In addition to potential application in the treatment of congenital epithelial dystrophies this technique may also provide new insights into LESC biology and the cellular dynamics of epithelial renewal.

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