The development of gene therapy for recessive dystrophic epidermolysis bullosa

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Epidermolysis bullosa (EB) is a group of inherited mechanobullous disorders characterised by trauma induced blistering. One of the most severe subtypes is recessive dystrophic epidermolysis bullosa (RDEB). RDEB is due to loss of function mutations in the gene encoding type VII collagen (COL7A1), one of the main constituents of anchoring fibrils anchoring the basement membrane to the underlying dermis. There is no cure for this devastating condition although promising pre-clinical studies for strategies using genetic correction, protein replacement, cell therapy or drug therapies are underway. Reconstitution of COL7A1 expression in both keratinocyte and fibroblast cell populations has been demonstrated using ex vivo gene therapy and hypothesised to lead to new anchoring fibril formation and amelioration of disease phenotype. Feasibility of this approach had been demonstrated in pre-clinical studies using a retroviral vector, and this work details the development of a phase 1 clinical trial to graft an autologous gene corrected skin equivalent graft. Detailed analysis of a cohort of adult patients with RDEB was performed in order to identify suitable trial candidates. In addition, an alternative strategy using a lentiviral vector encoding codon-optimised COL7A1 developed in order to transduce fibroblasts to be administered intradermally was developed. Expression and secretion of full-length de novo C7 was confirmed, with transduced cells exhibiting increased levels of protein expression despite only modest transduction efficiencies. This work details the journey and obstacles encountered in developing gene therapy clinical trials for RDEB, both through the development of a phase 1 study for an autologous gene corrected skin equivalent graft as well as a phase I study of intradermal autologous gene corrected fibroblasts.
Date of Award2017
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorJohn McGrath (Supervisor)

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