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Characterization of mitochondrial genetics in patients with age-related macular degeneration (AMD) may lead to personalized medicine approaches to treatment and the identification of novel therapeutic agents, said Baruch D. Kuppermann, MD, PhD, at the inaugural Retina World Congress.
“Although a lot is known about the nuclear genes associated with AMD, more is being learned about the mitochondrial DNA genome and about how the mitochondrial genes can affect nuclear gene expression," said Dr. Kuppermann, professor of ophthalmology and biomedical engineering, University of California, Irvine. "It is our fantasy that the information on relevant mitochondrial gene expression can be used to predict therapeutic outcomes.”
There are a number of reasons for focusing on the mitochondrial genome for insights about treatment of AMD. The first recognizes the importance of the mitochondria for maintaining retinal function.
“The retina has one of the highest oxygen consumption rates in the body and the cells need a lot of energy," Dr. Kupperman said. "We also know that the rods and cones contain numerous mitochondria in their inner segments.”
“It has been well known that reactive oxygen species (ROS) production, apoptosis, and energy production are key to mitochondrial function," he said. "Now, however, we are learning that there is retrograde signaling to the nuclei from the mitochondria, suggesting that targeting the mitochondria is an emerging approach to therapy.”
The idea of using mitochondrial genetics as a biomarker for AMD comes in part from evidence that there is significant mitochondrial damage in retinal specimens of eyes with AMD. Furthermore, increasing AMD severity has been shown to correlate with increasing mitochondrial DNA damage in RPE cells whereas the level of nuclear DNA damage seems to be unchanged.
In working toward translating these findings to personalized patient care, Dr. Kuppermann and colleagues are creating AMD “cybrids” to analyze the functional consequences of mitochondrial DNA variants. The cybrids are hybrids of immortalized human retina epithelial cells (ARPE-19) that contain their native nuclear DNA but the mitochondrial DNA of a patient with AMD.
Current studies are investigating the hypothesis that retinal cells with different mitochondria will respond differently to anti-VEGF medications and that the mitochondria have retrograde signaling capacity that influences levels of ROS and expression of genes related to angiogenesis and anti-oxidant pathways.
So far, analyses have been completed using cybrids created from just a few patients with AMD. Dr. Kuppermann showed the findings from two cases where the AMD phenotypes and findings from biochemical and molecular assays were correlated to the individual clinical histories.
One of the cases was a patient with wet AMD who had a very good response to anti-VEGF treatment but subsequently developed geographic atrophy. The cybrid analyses showed upregulation of ROS, which might have promoted geographic atrophy development, and downregulation of VEGF and hypoxia inducible factor 1-alpha, which was consistent with the good response to anti-VEGF therapy, Dr. Kuppermann said.
The second patient was also being treated for wet AMD, but had a poorer response. The cybrid analyses showed downregulation of ROS but upregulation of VEGF, consistent with the patient’s resistance to anti-VEGF treatment, Dr. Kuppermann said.
“We are now working to expand our catalogue of AMD cybrids and also to develop a catalogue of cybrids for diabetic macular edema (DME), and we are also trying to develop faster throughput so that the testing can be done more rapidly,” he said.
“Ultimately, we hope this work will allow us to predict clinical response to anti-VEGF therapy for AMD or to determine if anti-VEGF therapy or a corticosteroid is preferred for DME," Dr. Kuppermann said. "Potentially, this work can also be a model to find pharmacotherapeutic agents that may protect against mitochondrial DNA damage from AMD and DME.”