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Improving retinal mitochondrial function as a treatment for age-related macular degeneration.

ABSTRACT: Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly. Currently, there are no treatments for dry AMD, which is characterized by the death of retinal pigment epithelium (RPE) and photoreceptors. Reports from human donors with AMD suggest that RPE mitochondrial defects are a key event in AMD pathology. Thus, the most effective strategy for treating dry AMD is to identify compounds that enhance mitochondrial function and subsequently, preserve the RPE. In this study, primary cultures of RPE from human donors with (n = 20) or without (n = 8) AMD were used to evaluate compounds that are designed to protect mitochondria from oxidative damage (N-acetyl-l-cysteine; NAC), remove damaged mitochondria (Rapamycin), increase mitochondrial biogenesis (Pyrroloquinoline quinone; PQQ), and improve oxidative phosphorylation (Nicotinamide mononucleotide, NMN). Mitochondrial function measured after drug treatments showed an AMD-dependent response; only RPE from donors with AMD showed improvements. All four drugs caused a significant increase in maximal respiration (p < 0.05) compared to untreated controls. Treatment with Rapamycin, PQQ, or NMN significantly increased ATP production (p < 0.05). Only Rapamycin increased basal respiration (p < 0.05). Notably, robust responses were observed in only about 50% of AMD donors, with attenuated responses observed in the remaining AMD donors. Further, within the responders, individual donors exhibited a distinct reaction to each drug. Our results suggest drugs targeting pathways involved in maintaining healthy mitochondria can improve mitochondrial function in a select population of RPE from AMD donors. The unique response of individual donors to specific drugs supports the need for personalized medicine when treating AMD.

SUBMITTER: Ebeling MC

PROVIDER: S-EPMC7327959 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Improving retinal mitochondrial function as a treatment for age-related macular degeneration.

Ebeling Mara C MC Polanco Jorge R JR Qu Jun J Tu Chengjian C Montezuma Sandra R SR Ferrington Deborah A DA

Redox biology 20200518

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly. Currently, there are no treatments for dry AMD, which is characterized by the death of retinal pigment epithelium (RPE) and photoreceptors. Reports from human donors with AMD suggest that RPE mitochondrial defects are a key event in AMD pathology. Thus, the most effective strategy for treating dry AMD is to identify compounds that enhance mitochondrial function and subsequently, preserve the RPE. In this ...[more]

PMID: 32446621

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Project description:PurposeTo compare the efficacy of problem-solving therapy (PST) with supportive therapy (ST) to improve targeted vision function (TVF) in age-related macular degeneration (AMD).DesignSingle-masked, attention-controlled, randomized clinical trial with outcome assessments at 3 months (main trial endpoint) and 6 months (maintenance effects).ParticipantsPatients with AMD (n = 241) attending retina practices.InterventionsWhereas PST uses a structured problem-solving approach to reduce vision-related task difficulty, ST is a standardized attention-control treatment.Main outcome measuresWe assessed TVF, the 25-item National Eye Institute Vision Function Questionnaire plus Supplement (NEI VFQ), the Activities Inventory (AI), and vision-related quality of life (QoL).ResultsThere were no between-group differences in TVF scores at 3 (P = 0.47) or 6 (P = 0.62) months. For PST subjects, mean ± standard deviation TVF scores improved from 2.71±0.52 at baseline to 2.18±0.88 at 3 months (P = 0.001) and were 2.18±0.95 at 6 months (change from 3 to 6 months, P = 0.74). For ST subjects, TVF scores improved from 2.73±0.52 at baseline to 2.14±0.96 at 3 months (P = 0.001) and were 2.15±0.96 at 6 months (change from 3 to 6 months, P = 0.85). Similar proportions of PST and ST subjects had less difficulty performing a TVF goal at 3 months (77.4% vs 78.6%, respectively; P = 0.83) and 6 months (76.2% vs 79.1%, respectively; P = 0.61). There were no changes in the NEI VFQ or AI. Vision-related QoL improved for PST relative to ST subjects at 3 months (F(4, 192) = 2.46; P = 0.05) and at 6 months (F(4, 178) = 2.55; P = 0.05). The PST subjects also developed more adaptive coping strategies than ST subjects.ConclusionsWe found that PST was not superior to ST at improving vision function in patients with AMD, but that PST improved their vision-related QoL. Despite the benefits of anti-vascular endothelial growth factor treatments, AMD remains associated with disability, depression, and diminished QoL. This clinical reality necessitates new rehabilitative interventions to improve the vision function and QoL of older persons with AMD.Financial disclosure(s)The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Dataset Information

Improving retinal mitochondrial function as a treatment for age-related macular degeneration.

Publications

Improving retinal mitochondrial function as a treatment for age-related macular degeneration.

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