Exploration of gene therapies targeting oxidative stress and NAD+ pathways for the treatment of optic neuropathy
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2024-10-27Citation:
Finnegan, Laura Katharine, Exploration of gene therapies targeting oxidative stress and NAD+ pathways for the treatment of optic neuropathy, Trinity College Dublin, School of Genetics & Microbiology, Genetics, 2022Download Item:
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Abstract:
The World Health Organisation estimates that there are approximately 300 million people suffering from some form of blindness, from inherited retinal degenerations to complex diseases such as glaucoma. The vast heterogeneity of genetic forms of blindness coupled with the many contributing factors in complex diseases presents a hurdle in the development of treatments: it is challenging and economically unfeasible to develop gene-specific therapies for each disease, and so many patients are left without treatment options. However, targeting common pathways implicated in these diseases allows the exploration of therapies that may be applicable to wider cohorts of patients.
This thesis outlines three gene-independent therapeutic approaches that target the declining NAD+ levels and increasing oxidative stress seen in many neurodegenerative conditions and indeed in aging. Energy production through oxidative phosphorylation is a main source of reactive oxygen species (ROS). Age-related or disease-related deficits in mitochondrial function exacerbates ROS production, resulting in oxidative damage to cellular components. NAD+ serves as a key cofactor for many enzymes and an electron acceptor in redox reactions, with perturbations to NAD+ levels having implications on cellular activities from DNA repair to calcium homeostasis. Recently, NAD+ has been found to have a role in maintenance of axons and protection against Wallerian degeneration. Through boosting NAD+ metabolism and limiting oxidative damage, these therapies may be applicable to a wide range of diseases. Here, their impact on retinal ganglion cells (RGCs) was assessed in a chemically-induced model of optic neuropathy. Rotenone, a complex I inhibitor, was injected intravitreally to induce mitochondrial dysfunction in RGCs and their axons, which form the optic nerve.
The studies outlined in this thesis detail the potential of three gene-independent therapeutic approaches that are shown to improve mitochondrial function in vitro and protect against mitochondrial degeneration induced by rotenone in vivo. Through boosting NAD+ metabolism and limiting oxidative damage, these gene therapies are of therapeutic potential for the treatment of a host of neurodegenerative conditions, including inherited optic neuropathies and multifactorial conditions such as glaucoma. By targeting common pathways in many diseases, these therapies may be applicable to a wide cohort of patients.
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Irish Research Council
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https://tcdlocalportal.tcd.ie/pls/EnterApex/f?p=800:71:0::::P71_USERNAME:LAFINNEGDescription:
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Author: Finnegan, Laura Katharine
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Farrar, GwynethPublisher:
Trinity College Dublin. School of Genetics & Microbiology. Discipline of GeneticsType of material:
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