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Nazia Alam, Kristine Tsantilas, Whitney M. Cleghorn, Austin M. Rountree, Celia Bisbach, Brian Robbings, Martin Sadilek, Ian R. Sweet, Jim Hurley, Glen Prusky; SS-31 ameliorates age-induced visual decline and cone-mediated retinal dysfunction.. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4279.
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© ARVO (1962-2015); The Authors (2016-present)
Age-related visual decline and retinal disease make a large contribution to disability and have resisted effective treatment. In light of evidence that mitochondrial function declines in the visual system with age, we investigated in mice whether a therapeutic intervention thought to improve mitochondrial function can prevent or treat age-related visual and retinal dysfunction.
Spatial visual function of C57Bl/6 mice in photopic and scotopic lighting conditions was measured over the adult lifespan using a virtual optokinetic system. SS-31, a peptide that targets the inner mitochondrial membrane was administered (1-3mg/kg) at different ages and for varying lengths of time. The drug was administered via single or daily injections, or eye drops, or minipumps. To identify the physiological basis of behavioral changes, electroretinogram measures were made prior to euthanasia, and metabolic flux and O2 consumption measures were made in retinas and eyecups ex vivo.
Impaired photopic acuity emerged near 18 months, and declined ~60% by 34 months. Daily application of SS-31 initiated at 18 months mitigated subsequent visual decline. When initiated at 24 months, an age when spatial frequency thresholds were reduced by about 16%, daily SS-31 returned photopic function to adult norms within 2 months. Recovered function persisted for at least 3 months after treatment was withdrawn. A single treatment at 24 months also delayed subsequent visual decline. The effect of daily application from 32 months was less efficacious, but still enabled improvement within 2 months. The effects of age and treatment on contrast sensitivity was similar to those on acuity, and systemic and eye drop applications of SS-31 had comparable effects. Scotopic spatial visual function was largely unaffected by age or treatment. Altered function was independent of variation in optical clarity. Metabolic flux from 13C glucose through glycolysis and into mitochondria and O2 consumption were unaffected by SS-31 treatment. The dominant source of retinal change appears to be mediated through cone circuitry, which was confirmed with flicker fusion ERGs that show an improvement in the critical flicker fusion frequency after SS-31 treatment.
SS-31 treatment adaptively alters the aging visual system, which provides a rationale to investigate its use to treat pathophysiologies of human visual aging and age-related visual disease.
This is a 2020 ARVO Annual Meeting abstract.
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