Abstract
A primary pathological defect in the heritable eye disorder Stargardt disease is excessive accumulation of cytotoxic lipofuscin bisretinoids in the retina. Age-dependent accumulation of lipofuscin in the retinal pigment epithelium (RPE) matches the age-dependent increase in the incidence of the atrophic (dry) form of age-related macular degeneration (AMD) and therefore may be one of several pathogenic factors contributing to AMD progression. Lipofuscin bisretinoid synthesis in the retina depends on the influx of serum retinol from the circulation into the RPE. Formation of the tertiary retinol-binding protein 4 (RBP4)-transthyretin-retinol complex in the serum is required for this influx. Herein, we report the pharmacological effects of the non-retinoid RBP4 antagonist, BPN-14136. BPN-14136 dosing in the Abca4-/- mouse model of increased lipofuscinogenesis significantly reduced serum RBP4 levels and inhibited bisretinoid synthesis, and this inhibition correlated with a partial reduction in visual cycle retinoids such as retinaldehydes serving as bisretinoid precursors. BPN-14136 administration at doses inducing maximal serum RBP4 reduction did not produce changes in the rate of the visual cycle, consistent with minimal changes in dark adaptation. Abca4-/- mice exhibited dysregulation of the complement system in the retina, and BPN-14136 administration normalized the retinal levels of proinflammatory complement cascade components such as complement factors D and H, C-reactive protein, and C3. We conclude that BPN-14136 has several beneficial characteristics, combining inhibition of bisretinoid synthesis and reduction in retinaldehydes with normalization of the retinal complement system. BPN-14136, or a similar compound, may be a promising drug candidate to manage Stargardt disease and dry AMD.
Highlights
A primary pathological defect in the heritable eye disorder Stargardt disease is excessive accumulation of cytotoxic lipofuscin bisretinoids in the retina
Blueprint Neurotherapeutics (BPN)-14136 dosing in the Abca4؊/؊ mouse model of increased lipofuscinogenesis significantly reduced serum retinol-binding protein 4 (RBP4) levels and inhibited bisretinoid synthesis, and this inhibition correlated with a partial reduction in visual cycle retinoids such as retinaldehydes serving as bisretinoid precursors
Our efforts led to the discovery of the novel RBP4 antagonist BPN-14136, which contains a pyrimidine-4-carboxylic acid appended to a bicyclic [3.3.0]-octahydrocyclopenta[c]pyrrolo core (Fig. 1) [37]
Summary
Dept. of Ophthalmology, Columbia University Medical Center, 635 West 165th St., Box 27, New York, NY 10032. Characterization of novel non-retinoid RBP4 antagonist for macular degeneration would normalize complement system dysregulation in the retina and ameliorate symptoms of retinaldehyde toxicity prolonging RPE and photoreceptor survival in a patient’s retina. Assuming that accumulation of cytotoxic lipofuscin bisretinoids contributes to the disease pathology, it was hypothesized that pharmacological inhibition of bisretinoid formation by small molecule drugs may provide a means by which to delay or suppress degenerative processes in Stargardt disease and AMD [25,26,27,28,29]. We describe the in vivo efficacy of BPN14136 in inducing partial reduction of serum RBP4 and visual cycle retinoids such as retinaldehydes, robust inhibition of bisretinoid synthesis, and normalization of complement system. We report that positive attributes of BPN-14136 are not associated with inhibition of the visual cycle or significant suppression of the visual function in darkadapted eyes, which is consistent with the favorable ocular safety profile of compounds from this pharmacological class
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