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

https://www.sciencedirect.com/science/article/pii/S221323172030094X

Published:           July 2020

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

  1. protect mitochondria from oxidative damage (N-acetyl-L-cysteine; NAC),
  2. remove damaged mitochondria (Rapamycin),
  3. increase mitochondrial biogenesis (Pyrroloquinoline quinone; PQQ), and
  4. improve oxidative phosphorylation (Nicotinamide mononucleotide, NMN).

Mitochondrial function measured after drug treatments showed an AMDdependent 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.

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