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Xiaozhen J. Wang, Jennifer F. Nemeth, Nazneen Bano, James Dixon, Sicco H. Popma, Ian R. Harris; Potential Pharmacodynamic Biomarker For Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1804.
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Macular degeneration is the leading cause of blindness worldwide. Stargardt’s disease is a juvenile form of macular degeneration, and its etiology is clear. A mutation in a member of the ATP-binding cassette family (ABCA4) causes the dysfunction of this lipid transporter in the visual cycle of lipid turnover in the eye and leads to an increased production of A2E. This phenomenon was also observed in age-related macular degeneration. The accumulation of A2E in retinal pigment epithelial cells (RPE) may lead to mitochondrial oxidative dysfunction and cell death in RPE, and eventually causes photoreceptor cell death and blindness. As an eye-specific molecule, A2E may be a marker for tracking the stage of disease.
A2E toxic effect was studied in vitro using ARPE-19 cell line. In Royal College of Surgeon's (RCS) rat model, gene expression of ABCA4, related to A2E production, was measured in normal, dystrophic, and dystrophic with treatment conditions. Lipid and metabolite profiling were performed in eye tissue and plasma from RCS rats.
In this study we confirmed that A2E stimulated RPE cell death in culture and can be an etiology of macular degeneration. In addition, in a retinal degeneration animal model, ABCA4 was down-regulated in eyes with severe disease, simulating the dysfunction of ABCA4 in Stargardt's disease. Using a metabolomics approach followed by pathway analysis, the mitochondrial oxidative pathway was also found to be affected in animals with severe disease. Similar results were observed in lipidomics analysis in the eye tissue and plasma. A therapy that was able to maintain the level of ABCA4 in the eyes and improved oxidative pathway in mitochondria demonstrated preservation of photoreceptors and by extension, vision.
Thus, the production of A2E and its effect on mitochondrial oxidative pathway could be the target of a therapy to preserve retina and improve vision. Additionally, based on these in vitro and in vivo observations, A2E and markers from the mitochondrial oxidative pathway may be utilized as pharmacodynamic biomarkers to demonstrate early therapeutic effect in macular degeneration patients.
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