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Mitochondrial therapy against diabetic retinopathy
thesisposted on 2023-05-28, 09:44 authored by Daniel, AO
Diabetic retinopathy (DR) is a common vascular complication of diabetes and one of the leading causes of blindness. Up to 80% of chronic cases of diabetes develop diabetic retinopathy. Current treatment options are largely directed towards DR-associated symptoms, such as counteracting inflammation and reducing vascular endothelial growth factor-induced angiogenesis. Unfortunately, managing vision loss in diabetic patients using these approaches has not been very effective; with less than 30% of patients responding by a significant improvement of their visual function. Although, not all pathophysiological processes, which underlie the development of DR are fully elucidated, mounting evidence points towards a central role of hyperglycaemia-induced mitochondrial dysfunction in its aetiology. Central to this hypothesis is mitochondrially-generated oxidative stress, which in turn stimulates other processes like the activation of protein kinase C, increased flux in polyol and hexosamine pathways, increased formation of advanced glycation end-products and reduced ATP levels. It is hypothesized that these processes result in retinal vascular damage, leading to vascular permeability, microaneurysms, angiogenesis, degeneration of capillaries and eventual retinal ganglion cell death. Overall, there is an urgent need to develop new therapies that are not restricted to symptomatic treatments but instead address one of the central pathologies of the disease, mitochondrial dysfunction. Currently, only one mitochondrial therapy, Elamipretide, has been trialled in a mouse model of diabetic retinopathy, where it reversed mild loss of vision. However, other mitochondrial therapies such as idebenone (Raxone¬¨vÜ) and SkQ1 (Visomitin¬¨vÜ) are already available commercially for the treatment of Leber's Hereditary Optic Neuropathy (LHON) and dry eye syndrome, respectively, which could provide a rapid bench to bedside transition. Consequently, in this study I hypothesised that drug candidates that aim to normalize mitochondrial function, restore energy homeostasis and counteract oxidative stress are an attractive proposition as potential novel treatments against diabetic retinopathy. To test this hypothesis, I performed the first side-by side comparison of the mitoprotective idebenone against two novel short-chain quinones (SCQs) and Elamipretide in a rat model of diabetic retinopathy. The two novel cytoprotective SCQs tested in this in-vivo study, were identified in a previous in-vitro study as drug candidates with improved cytoprotective activity against mitochondrial dysfunction compared to idebenone. Using a recently described pre-clinical rat model, based on the administration of streptozocin (STZ) via osmotic mini-pumps, I effectively mimicked sustained type 2-like diabetes in adult male Long Evans rats that resembled the human phenotype of DR. This animal model was characterized by polydipsia, polyuria, increased food intake, hyperglycaemia and severe vision loss. Three weeks of topical treatment with all test compounds via eye drops significantly improved visual acuity without affecting hyperglycaemia, while visual acuity in the vehicle- treated animals continued to deteriorate. Although, all test compounds protected against diabetes-induced retinal ganglion cells loss, thinning of the retinal layer and oxidative tissue damage, our novel SCQs were superior to idebenone and Elamipretide with regards to restoring visual acuity and protecting against loss of retinal ganglion cells. However, the specific mechanism(s) by which the test compounds exerted their protective effects in this study remains unclear at present and will likely require further detailed studies. In conclusion, my results highlight that mito-protective SCQs have significant potential as drug candidates that could be developed as novel therapeutic options against DR and other related ophthalmological indications.
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