Systemic administration of the di-apocarotenoid norbixin (BIO201) is neuroprotective, preserves photoreceptor function and inhibits A2E and lipofuscin accumulation in animal models of age-related macular degeneration and Stargardt disease.

Valérie Fontaine,Thinhinane Boumedine,Elodie Monteiro,Louis Guibout,René Lafont,Elena Brazhnikova,Cécile Vidal,Stanislas Veillet,Christine Balducci,Mylène Fournié,Pierre J Dilda,Mathilde Latil,Serge Camelo,José-Alain Sahel

doi:10.18632/aging.103014

Abstract

Atrophic A\\age-related macular degeneration (AMD) and Stargardt disease (STGD) are major blinding diseases affecting millions of patients worldwide, but no treatment is available. In dry AMD and STGD oxidative stress and subretinal accumulation of N-retinylidene-N-retinylethanolamine (A2E), a toxic by-product of the visual cycle, causes retinal pigment epithelium (RPE) and photoreceptor degeneration leading to visual impairment. Acute and chronic retinal degeneration following blue light damage (BLD) in BALB/c mice and aging of Abca4-/- Rdh8-/- mice, respectively, reproduce features of AMD and STGD. Efficacy of systemic administrations of 9'-cis-norbixin (norbixin), a natural di-apocarotenoid, prepared from Bixa orellana seeds with anti-oxidative properties, was evaluated during BLD in BALB/c mice, and in Abca4-/- Rdh8-/- mice of different ages, following three experimental designs: “preventive”, “early curative” and “late curative” supplementations. Norbixin injected intraperitoneally in BALB/c mice, maintained scotopic and photopic electroretinogram amplitude and was neuroprotective. Norbixin chronic oral administration for 6 months in Abca4-/- Rdh8-/- mice following the “early curative” supplementation showed optimal neuroprotection and maintenance of photoreceptor function and reduced ocular A2E accumulation. Thus, norbixin appears promising as a systemic drug candidate for both AMD and STGD treatment.

Highlights

Age-related macular degeneration (AMD) is the commonest cause of severe visual loss and blindness in developed countries among individuals aged 60 and older [1]
Norbixin protects primary porcine retinal pigment epithelium (RPE) cells against phototoxicity induced by A2E and blue-light illumination in vitro [22]
To determine whether norbixin could protect the retina via a systemic effect we used a model of blue light damage (BLD) in albino BALB/c mice

Summary

Introduction

Age-related macular degeneration (AMD) is the commonest cause of severe visual loss and blindness in developed countries among individuals aged 60 and older [1]. STGD is the most common hereditary macular dystrophy, mostly affecting young patients aged between 6 and 15 years old with a prevalence of 1/8,000-1/10,000 [2, 3]. It has an autosomal recessive mode of inheritance and may lead to registered blindness within the second or third decade of life. Despite some differences, dry AMD and STGD share similar pathophysiological mechanisms [11] In both pathologies, early signs of evolution are characterized by subretinal accumulation of lipids and proteins forming drusen in AMD and flecks in STGD [2, 12]. No treatment is available for either STGD [11] or dry AMD [15]

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Results

Conclusion