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J Biol Chem. 2018 Jul 20;293(29):11574-11588. doi: 10.1074/jbc.RA118.002062. Epub 2018 Jun 5.

A non-retinoid antagonist of retinol-binding protein 4 rescues phenotype in a model of Stargardt disease without inhibiting the visual cycle.

Author information

1
From the Departments of Ophthalmology and.
2
Pathology and Cell Biology, Columbia University, New York, New York 10032.
3
the Pearson Pharma Partners, Westlake Village, California 91361.
4
NuPharmAdvise LLC, Sanbornton, New Hampshire 03269, and.
5
the Departments of Basic and Clinical Sciences and Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Albany, New York 12208.
6
From the Departments of Ophthalmology and kep4@cumc.columbia.edu.

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.

KEYWORDS:

RBP4; Stargardt disease; age-related macular degeneration; drug design; drug development; drug discovery; lipofuscin; molecular pharmacology; pharmacokinetics; pharmacology; retina; retinal degeneration; retinal metabolism; retinoid-binding protein; visual cycle

PMID:
29871924
PMCID:
PMC6065170
[Available on 2019-07-20]
DOI:
10.1074/jbc.RA118.002062
[Indexed for MEDLINE]

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