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Marcelo Nociari; Beta cyclodextrins bind and remove Lipofuscin Bisretinoids from RPE. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3297.
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Lipofuscin bisretinoids (LBs) accumulate irreversibly in the lysosomes of Retinal Pigment Epithelium (RPE) cells with age and in some genetic diseases, such as Stargardt and Best diseases. Excessive LB accumulation is toxic and causes retinal degeneration. The goal of this study is to develop a small drug to reduce the levels of LBs from RPE.
Using a novel solvatochromic fluorescence shift screening assay, we just developed, we searched for small molecules with ability to bind the most abundant LB, A2E.
We have identified beta cyclodextrins (β-CDs), cyclic rings formed by 7 glucose residues, as small drugs that bind A2E. We show that treatment with beta-CDs stabilizes A2E by preventing its oxidation, and reduces bisretinoid content from lipofuscin granules in RPE. Molecular modeling of the complex indicate strategies to improve the LB binding of CDs. Furthermore, we tested the removal properties of CDs in eyes of ABCA4/RDH8 DKO animals, a mouse model for LB-driven retinal degeneration, and observed a reduction in bisretinoid levels larger than 60%.
These results provide important clues to develop a novel small drug therapy to preserve and/or improve retinal function in individuals with LB driven retinal degeneration.
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