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

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.

• Authors: Boglarka Racz, Andras Varadi, Jian Kong, Rando Allikmets, Paul G Pearson, Graham Johnson, Christopher L Cioffi, Konstantin Petrukhin
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 293 Issue 29 Pg. 11574-11588 (07 20 2018) ISSN: 1083-351X [Electronic] United States
• PMID: 29871924 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Racz et al.

Chemical References

• BPN-14136
• Carboxylic Acids
• Lipofuscin
• Pyrimidines
• Pyrroles
• Rbp4 protein, mouse
• Retinoids
• Retinol-Binding Proteins, Plasma
• Rhodopsin

Topics

• Animals
• Carboxylic Acids (pharmacology, therapeutic use)
• Dark Adaptation (drug effects)
• Disease Models, Animal
• Lipofuscin (metabolism)
• Male
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Pyrimidines (pharmacology, therapeutic use)
• Pyrroles (pharmacology, therapeutic use)
• Retina (drug effects, metabolism, pathology)
• Retinoids (metabolism)
• Retinol-Binding Proteins, Plasma (antagonists & inhibitors, metabolism)
• Rhodopsin (metabolism)
• Stargardt Disease (drug therapy, pathology)