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Tatjana Taubitz, Tobias Peters, Simone Pöschel, Alexander Tschulakow, Monika Rittgarn, Sigrid Schultheiss, Katja Schenke-Layland, Michael Burnet, Sylvie Julien, Ulrich Schraermeyer; Removal of lipofuscin from the RPE of Abca4-/- mice with THPE: quantitative and toxicity studies. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4199.
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The accumulation of lipofuscin (LF) in the retinal pigment epithelium (RPE) is a hallmark of aging and is supposed to play a key role in the development of age-related macular degeneration (AMD) and Stargardt disease. We previously reported that tetrahydropyridoethers (THPE) are able to remove LF from monkey RPE cells in vivo and aged human donor RPE cells in vitro. Here we present that THPE are also effective in a mouse model for Stargardt disease and show no toxic effects.
In total, 55 pigmented Abca4-/- mice were intravitreally injected once with THPE or vehicle for control. For the quantitative study, eyes were either fixed and examined by light and electron microscopy or RPE cells were isolated and analyzed by imaging flow cytometry after two to six weeks. The area occupied by LF granules was quantified in 10 micrographs per eye on average. For the toxicity study, full-field electroretinographic examination (ERG, using scotopic single flash and scotopic flicker and photopic single flash followed by flicker series) was performed in 16 animals directly before (baseline) and one, two and four weeks after intravitreal injection. After four weeks, animals were sacrificed and the eyes were examined by light and electron microscopy, including quantification of photoreceptor nuclei.
A single treatment in 12-month-old animals resulted in a loss of ~50% (p<0.05) of the area occupied by LF compared to control after 3 weeks. In 6-month-old treated animals, there was no difference to control after 2 weeks, but after 6 weeks LF was reduced to ~25% (p<0.001). Two weeks after a single injection of 9-month-old animals with THPE, the number of cells with high LF autofluorescence was lower in treated eyes compared to control (p<0.05) as measured with imaging flow cytometry. THPE treatment showed no effect on the a- and b-wave amplitudes in ERG compared to control. Histologically, there were no aberrant changes in retinal morphology, in particular, there was no loss of photoreceptor nuclei after treatment.
THPE reduce the amount of LF not only in the healthy but also in the diseased RPE. Treatment with intravitreal THPE does not cause any toxic effects as shown by ERG and histological examination. This suggests that THPE compounds have an extraordinary potential as possible treatment options for LF-related diseases like dry AMD and Stargardt disease.
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