Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.746582
Title: Regeneration of ocular tissues using gene transfer
Author: Kampik, D.
ISNI:       0000 0004 7224 7328
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2017
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Please try the link below.
Access from Institution:
Abstract:
Gene therapy of the eye has made huge advances in recent years, which led to first clinical trials. While these were aimed at replacing a defective gene in inherited disease, research is now expanding to using augmentation gene therapy where a gene is used to modulate the course of disease. We investigated the possibilities of gene transfer of cell cycle modulating genes to induce proliferation in two amitotic tissues essential for vision, the corneal endothelium and retinal pigment epithelium. Corneal endothelial cells (CEC) maintain the water content of the cornea and thereby its clarity. Low CEC density in corneal diseases causes blindness and requires corneal transplantation. Transfer of E2F2, a transcription factor regulating G1 to S phase progression, increases CEC density in human ex vivo cultivated corneas, but only when transferred by adenoviral vector, not lentiviral vector. Instead, lentiviral overexpression of ZONAB, a transcription factor normally inactivated by tight junction protein ZO-1, increased CEC density. Lentiviral downregulation of ZO-1, mimicking loss of cell-cell contacts and loss of contact inhibition, led to CEC proliferation. However, CEC density increase was only achieved in young corneas up to ~60 years-of-age, indicating loss of proliferative capacity with age. RPE loss, as seen in age related macular degeneration (AMD), causes photoreceptor loss and blindness. RPE proliferation could be induced using non-integrating lentiviral vectors delivering E2F2. We showed this in vitro and in vivo after subretinal injection of vector in normal RPE of wildtype mice. To a certain extent, the proliferative effect could also be seen in a transgenic mouse model with degenerated RPE. This concept of in situ regeneration by induction of proliferation could lead to new strategies for CEC loss, especially in donor corneas stored in eye banks. For the RPE, it could be used for treatment of early stages of AMD.
Supervisor: Ali, R. R. ; Larkin, D. F. P. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.746582  DOI: Not available
Share: