Abstract
Age-related macular degeneration (AMD) is a complex multifaceted eye disease and is one of the most common causes of vision impairment in the aging population of developed countries. Its pathology includes the dysregulation of retinal pigment epithelium (RPE) and Bruch's membrane, which leads to the loss of photoreceptors, the photosensitive cells of the retina. Of the two types: dry-AMD and wet-AMD or exudative neovascular AMD (nAMD): nAMD is the most aggressive, resulting from aberrant choroidal blood capillary growth into the retina, known as choroidal neovascularization (CNV). This growth results in leaky blood vessels causing increased buildup of fluid and blood into the retina, so disrupting retinal integrity and RPE cell function, leading to the death of RPE and photoreceptor cells. The myriad pathological features that describe AMD are fuelled by an increase in oxidative stress, inflammation and the activation of the immune system, identified as key elements in AMD pathology. While there are limited treatment options for dry-AMD, treatment options of nAMD are invasive and demanding, highlighting the need for novel and individualized therapies. However, this alone presents immense challenges, and a detailed analysis of retinal biomarkers that describe in detail, disease development, progression and monitoring of the disease and therapeutic intervention is critical.Retinal biomarkers are described as distinct biological signatures within the retina that can be measured and analysed to detect, monitor and predict the progression of disease, such as AMD. This research first aimed to establish a laser-induced CNV model to investigate functional and structural retinal biomarkers as key indicators of CNV progression, over an extended period of 28 days. Detailed investigation into retinal function was established and analysed with electroretinography, which measures the electrical response of the retina to light stimulation. A functional profile of the a-wave, b-wave and oscillatory potentials was evaluated, revealing changes specific to individual cell types. Following this, fundus fluorescein angiography confirmed induction of CNV and vascular remodelling at both an early and late phase of CNV development. Retinal integrity was imaged with optical coherent technology, detailing in vivo retinal structural changes, and novel retinal biomarkers becoming apparent, described as hyperreflective foci. Furthermore, histology confirmed the induction of oxidative stress and inflammation in the laser-induced CNV model.
In response to identifying retinal biomarkers, this research aims to validate their significance by examining their changing profile following exposure to a new compound in the established model. The study focuses on the use of a novel compound, NOXAI, a hybrid dual acting drug specifically designed to target biological pathways related to oxidative stress and inflammation within the retina. By observing how NOXAI affects these retinal biomarkers, the research seeks to confirm their reliability as indicators of retinal health and drug effectiveness.
By uncovering the symbiotic relationship of functional, structural retinal biomarkers and histopathological evaluation over an extended time course in the laser-induced CNV model, this thesis provides valuable insight into the complexity of a disease like nAMD. This research reveals novel information about the profile and stages of CNV development and identifies potential timepoints for therapeutic intervention. The work lays the foundation for translational applications to monitor and predict effective and personalized treatment regimens for AMD sufferers.
| Date of Award | 2024 |
|---|---|
| Original language | English |
| Supervisor | Nigel Barnett (Supervisor) & Helen O'Neill (Supervisor) |