norbixin and Macular-Degeneration

Age-related macular degeneration (AMD) is the commonest cause of severe visual loss and blindness in developed countries among individuals aged 60 and older. AMD slowly progresses from early AMD to intermediate AMD (iAMD) and ultimately late-stage AMD. Late AMD encompasses either neovascular AMD (nAMD) or geographic atrophy (GA). nAMD is defined by choroidal neovascularization (CNV) and hemorrhage in the subretinal space at the level of the macula. This induces a rapid visual impairment caused by the death of photoreceptor cells. Intravitreal injection of anti-vascular endothelial growth factor (VEGF) antibodies is the standard treatment of nAMD but adds to the burden of patient care. GA is characterized by slowly expanding photoreceptor, and retinal pigment epithelium (RPE) degeneration patches progressively leading to blindness. There is currently no therapy to cure GA. Late AMD continues to be an unmet medical need representing a major health problem with millions of patients worldwide. Oxidative stress and inflammation are recognized as some of the main risk factors to developing late AMD. The antioxidant formulation AREDS (Age-Related Eye Disease Studies), contains

Topics: Aged; Aged, 80 and over; Anti-Inflammatory Agents; Antioxidants; Carotenoids; Disease Progression; Humans; Macular Degeneration; Middle Aged; Retinal Pigment Epithelium; Severity of Illness Index

Topics: Angiogenesis Inhibitors; Animals; Carotenoids; Humans; Macular Degeneration; Neovascularization, Pathologic; PPAR alpha; PPAR delta; PPAR gamma; PPAR-beta; Retinal Pigment Epithelium; Retinoid X Receptors; Retinoids; Swine; Vascular Endothelial Growth Factor A

The accumulation of N-retinylidene-N-retinylethanolamine (A2E, a toxic by-product of the visual pigment cycle) in the retinal pigment epithelium (RPE) is a major cause of visual impairment in the elderly. Photooxidation of A2E results in retinal pigment epithelium degeneration followed by that of associated photoreceptors. Present treatments rely on nutrient supplementation with antioxidants. 9'-cis-Norbixin (a natural diapocarotenoid, 97% purity) was prepared from Bixa orellana seeds. It was first evaluated in primary cultures of porcine retinal pigment epithelium cells challenged with A2E and illuminated with blue light, and it provided an improved photo-protection as compared with lutein or zeaxanthin. In Abca4-/- Rdh8-/- mice (a model of dry AMD), intravitreally-injected norbixin maintained the electroretinogram and protected photoreceptors against light damage. In a standard rat blue-light model of photodamage, norbixin was at least equally as active as phenyl-N-tert-butylnitrone, a free radical spin-trap. Chronic experiments performed with Abca4-/- Rdh8-/- mice treated orally for 3 months with norbixin showed a reduced A2E accumulation in the retina. Norbixin appears promising for developing an oral treatment of macular degeneration. A drug candidate (BIO201) with 9'-cis-norbixin as the active principle ingredient is under development, and its potential will be assessed in a forthcoming clinical trial.

Topics: Alcohol Oxidoreductases; Animals; ATP-Binding Cassette Transporters; Bixaceae; Carotenoids; Cells, Cultured; Disease Models, Animal; In Vitro Techniques; Intravitreal Injections; Macular Degeneration; Mice; Mice, Knockout; Photoreceptor Cells, Vertebrate; Plant Extracts; Rats; Retinal Pigment Epithelium; Retinoids; Swine