An Exploration of Mitochondrially Targeted Gene Therapies for Ocular Disorders
Embargo End Date:2022-01-22
Citation:MALONEY, DANIEL MANRAJ, An Exploration of Mitochondrially Targeted Gene Therapies for Ocular Disorders, Trinity College Dublin.School of Genetics & Microbiology, 2020
Mitochondria play a vital role in numerous fundamental processes of the cell such as ATP synthesis, cellular signalling, reactive oxygen species production, calcium regulation and apoptosis to name but a few. Given their central role in cellular homeostasis, mitochondria are increasingly being implicated in a wide array of diseases due to a broad range of primary mitochondrial mutations. Furthermore, there is increasing evidence of mitochondrial dysfunction in disorders not directly due to primary heritable mitochondrial mutations but rather resulting from dysregulation of the myriad of functions that mitochondria undertake; these disorders include Alzheimer's disease, Parkinson's disease and Multiple Sclerosis, among others. The eye, and in particular the retina, is a highly energetic tissue requiring significant levels of ATP production to stay active and as such is exquisitely sensitive to disturbances in mitochondrial function. This can be seen in the primary heritable mitochondrial disorders that affect the eye, such as Leber Hereditary Optic Neuropathy and Dominant Optic Atrophy. However, the mitochondrion's role in more complex ocular diseases such as Glaucoma and Age-related Macular degeneration has recently come to the fore. The primary aim of the studies described in this PhD thesis is to investigate novel gene therapy approaches for modulating mitochondrial function in ocular disorders. As there are currently over 270 genes associated with inherited retinal degenerations, potential therapies that can target common aspects between these disorders will be advantageous. This thesis focuses on three strategies to augment mitochondrial function; ectopically expressing Ndi1, a yeast complex I homologue, and an optimised version of Ndi1 to supplement NADH oxidation activity in vitro and in vivo, the use of OPA1, a mediator of mitochondrial fusion, to modulate mitochondrial network dynamics and restore functionality in OPA1 knockout cells, and the identification of a novel alternative oxidase protein and analysis of its functionality in vitro with its use in chemically induced models of mitochondrial dysfunction.
Author: MALONEY, DANIEL MANRAJ
Publisher:Trinity College Dublin. School of Genetics & Microbiology. Discipline of Genetics
Type of material:Thesis
Availability:Full text available