Age-related macular degeneration (AMD) is the leading cause of vision loss and legal blindness in higher-resourced countries. The progressive and degenerative disease—which causes irreversible vision loss—is caused by the dysfunction and death of the retinal pigment epithelium (RPE) and photoreceptors.

Now, induced pluripotent stem cells generated from AMD patients and healthy individuals were differentiated to RPE cells. These cells allowed for transcriptomics and proteomics approaches to identify molecular pathways significantly upregulated in one type of AMD— geographic atrophy. The findings point to processes such as mitochondrial functions, metabolic pathways, and extracellular cellular matrix reorganization. The discovery of new genetic signatures of the disease will lead to better diagnosis and treatment of AMD.

This work is published in Nature Communications in the paper, “Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration.”

“We’ve tested the way that differences in people’s genes impact the cells involved in age-related macular degeneration. At the smallest scale we’ve narrowed down specific types of cells to pinpoint the genetic markers of this disease,” said Joseph Powell, PhD, director of cellular science at the Garvan Institute of Medical Research. “This is the basis of precision medicine, where we can then look at what therapeutics might be most effective for a person’s genetic profile of disease.”

Fluorescent imaging of retinal pigment epithelium. [Grace Lidgerwood]
The researchers integrated transcriptional profiles of 127,659 RPE cells generated from 43 individuals with geographic atrophy (one of the two types of AMD) and 36 controls with genotype data.

RPE cells line the back of the retina and are essential to the health and functioning of the retina. Their degeneration is associated with the death of photoreceptors, which are responsible for the loss of vision in AMD.

Analysis of 127,659 cells revealed molecular signatures associated with AMD. More specifically, they identified 445 expression quantitative trait loci in cis that are associated with disease status and specific to RPE subpopulations.

The authors noted that five significant protein quantitative trait loci were identified—two of which share variants with cis-expression quantitative trait loci—including proteins involved in mitochondrial biology and neurodegeneration.

Further investigation of mitochondrial metabolism confirmed mitochondrial dysfunction as “a core constitutive difference of the retinal pigment epithelium from patients with geographic atrophy.”

The authors noted that the molecular signatures could potentially be used for screening of treatments using patient-specific cells in a dish. “Ultimately, we are interested in matching the genetic profile of a patient to the best drug for that patient. We need to test how they work in cells relevant to the disease,” said Alice Pébay, PhD, professor in the department of anatomy and physiology at the University of Melbourne.

“We have been building a program of research where we’re interested in stem cell studies to model disease at very large scale to do screening for future clinical trials,” said Alex Hewitt, BMedSci, MBBS, PhD, at the Menzies Institute for Medical Research in Tasmania and the Centre for Eye Research Australia. In another recent study, the researchers uncovered genetic signatures of glaucoma—a degenerative eye disease causing blindness—using stem cell models of the retina and optic nerve.

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