Investigation of pathomechanisms and treatment safety of age-related and juvenile macular degeneration

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Dokumentart: PhDThesis
Date: 2020-03-10
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biochemie
Advisor: Schraermeyer, Ulrich (Prof. Dr.)
Day of Oral Examination: 2020-03-03
DDC Classifikation: 570 - Life sciences; biology
610 - Medicine and health
Keywords: Netzhaut , Auge , Macula , Melanin , Makuladegeneration , Oxidativer Stress , Vascular endothelial Growth Factor , Lipopigment
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In humans, high-resolution vision relies on a specialised anatomical structure of the retina, the so called macula. While only 5.5 mm in diameter, the macula is indispensable for visual tasks depending on visual fixation of an object, such as reading and facial recognition. Loss of the macula therefore heavily impairs affected individuals, even though peripheral vision is not inhibited and spatial orientation is still possible. Macular degeneration usually arises either as multifactorial age-dependent disease (age-related macular degeneration, AMD) or as rare hereditary disease (the most common one being Stargardt disease, STGD1). AMD can be sub-classified in a “wet” (exudative) form that is characterised by neovascularisation with collateral oedema and bleeding, and a “dry” (non-exudative) form defined by local degeneration of photoreceptors, retinal pigment epithelium cells and the supporting capillary bed. Inherited Stargardt disease has a similar clinical presentation to dry AMD, even though the underlying disease mechanisms differ. To date, no cure for AMD or Stargardt disease is available. However, since wet AMD is accompanied with a surplus of growth factors, e.g. vascular endothelial growth factor (VEGF), the repeated intravitreal application of anti-VEGF therapeutics allows for a reversal of acute visual distortions due to oedema and a reduction of disease progression. This thesis deals with the pathologic processes and pharmacological therapy of macular degeneration and therefore investigates three aspects: 1) pathomechanisms in AMD and Stargardt disease, investigated by light- and electron microscopy on human donor samples and three Stargardt mouse models, respectively 2) resolving the subcellular origin of near-infrared autofluorescence (NIR-AF) used in diagnostics and monitoring of retinal diseases, such as AMD and STGD1 3) adverse events on the ultrastructural level after intravitreal use of antiVEGF compounds for treatment of wet AMD A light and electron microscopic investigation of human ocular tissue with and without AMD revealed that a loss of choriocapillaris, the nourishing capillary bed underneath the retina, precedes retinal degeneration in both the wet and the dry form of AMD. This study answered the open question of which retinal tissue is the first to degenerate in AMD. Stargardt disease progression was investigated in three commonly used Stargardt mouse models and revealed distinctive pathologic changes only present in an albino, but not in two pigmented mouse models, highlighting the potential beneficial impact of ocular melanin in disease modulation. NIR-AF was shown to not be an intrinsic property of melanin, as previously thought, but rather a consequence of melanin damage due to photic and/or oxidative stress. Furthermore, NIR-AF was found to not only stem from melanosomes, but also partly from lipofuscin, a byproduct of the visual cycle that accumulates with age and/or disease in the retinal pigment epithelium. These findings are relevant for both elucidating the pathomechanisms in melanin- and lipofuscinassociated retinal diseases and the refinement of NIR-AF based diagnostics. And lastly, previous ultrastructural investigations of adverse events of the immunoglobulin G (IgG)-based anti-VEGF compound bevacizumab suggested that the fragment crystallisable (Fc) unit is involved in the development of said adverse events. This was confirmed by studies analysing ultrastructural changes after intravitreal application of anti-VEGF compounds with and without Fc fragment in monkey eyes and intravitreal application of isolated Fc fragments in rat eyes. These works emphasize the role of the Fc fragment in adverse events of IgG-based pharmacological compounds used in ophthalmology. To conclude, the present thesis investigates key events in the pathomechanisms of AMD (order of tissue loss) and STGD1 (indicated protective role of melanin), identifies the subcellular origin of the NIR-AF signal used in ophthalmologic diagnostics and disease monitoring and confirms the involvement of the Fc fragment in adverse events observed after intravitreal application of anti-VEGF compounds.

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