Anderson, OA;
(2014)
Age-related macular degeneration:pathogenesis and drug delivery.
Doctoral thesis , UCL (University College London).
Abstract
Age related macular degeneration (AMD) is the leading cause of blindness amongst the elderly in the developed world. There is currently no effective treatment for the atrophic (dry) form of the disease. The aims of this thesis are twofold: Firstly to investigate the pathogenesis of atrophic AMD, a chronic inflammatory disease, with a view to identifying new potential treatment targets. Secondly to develop a novel method of sustained drug delivery with a view to using this mode of delivery to deliver immune modulating therapy in the treatment of atrophic AMD. We discovered that A2E, the major fluorophore of lipofuscin, induces the release of multiple chemokines and cytokines by retinal pigment epithelial cells in vitro. We showed that IL-1 1 was produced following activation of the NLRP3 inflammasome. Increased levels of IL-1 1 were also seen in the retinal-choroidal interface of ABCA4 knockout mice, known to contain high levels of A2E. A2E appears to be proinflammatory and therefore may be involved in the pathogenesis of age related macular degeneration. We also assessed the use of hyaluronic acid binding peptides as a mode of sustained intravitreal drug delivery. This was with the intention of linking them to a pharmacological agent, hence prolonging the intravitreal half-life of that agent. With regards to the peptide HABP35, we showed that hyaluronic acid binding translated into prolonged retention in the vitreous, in both an in vitro and in vivo setting. We then proposed a method of demonstrating its efficacy in vivo using IL-1 1 as a potential target. In conclusion our results provide novel data concerning a potential inflammatory role of A2E in the pathogenesis of AMD as well as introducing hyaluronic acid binding peptides into the field of ocular drug delivery.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | Age-related macular degeneration:pathogenesis and drug delivery |
| Language: | English |
| 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 Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1457066 |
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