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Konstantin Petrukhin, Boglarka Racz; Evaluation of the advanced antagonist of Retinol-Binding Protein 4 in animal models of bisretinoid and retinaldehyde toxicity. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1937.
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Dry AMD is a multifactorial disorder with several different pathogenic factors contributing to the disease progression. Age-dependent accumulation of cytotoxic lipofuscin in the retina matches the age-dependent increase in dry ADM prevalence and is frequently cited as one of potential pathogenic factors. An emerging complimentary view on the role of lipofuscin bisretinoids in dry AMD stresses the causative role of retinaldehyde toxicity in disease progression over the pathogenic contribution of lipofuscin bisretinoids. We identified several classes of novel non-retinoid antagonists of Retinol-Binding Protein 4 (RBP4). Here we describe characterization of the advance RBP4 antagonist in relevant animal models of bisretinoid and retinaldehyde toxicity.
The effect of compound dosing on lipofuscin bisretinoid synthesis was assessed in the Abca4-/- mice as well as in the double knock-out Abca4-/-Rdh8-/- mouse model following 3 months of dosing. The protective effect of compound dosing against combined bisretinoid and retinaldehyde toxicity was evaluated in the double knock-out Abca4-/-Rdh8-/- model by assessing ERG parameters and by measuring preservation of the photoreceptor layer.
Compound administration partially restricted retinol supply to the RPE and induced drastic inhibition of lipofuscin bisretinoid synthesis in eyecups of the Abca4-/- mice as well as in the retinas of double knock-out Abca4-/-Rdh8-/- mice. Compound administration inhibited photoreceptor degeneration and suppressed ERG attenuation in the Abca4-/-Rdh8-/- model.
The drug candidate drastically inhibited formation of lipofuscin bisretinoids and conferred anatomical and functional photoreceptor preservation in the model of combined bisretinoid and aldehyde toxicity. Our study indicates that this drug candidate may potentially be considered as a treatment for dry AMD and Stargardt disease.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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