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Valerie Fontaine, Elena Brazhnikova, Elodie Monteiro, Laëtitia Lesage, Christine Balducci, Louis Guibout, Laurence Feraille, Pierre-Paul Elena, Jose Sahel, Stanislas Veillet, René Lafont; BIO201: a new drug candidate for the treatment of dry AMD. Invest. Ophthalmol. Vis. Sci. 2016;57(12):1119.
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© 2017 Association for Research in Vision and Ophthalmology.
Dry AMD is a major cause of visual impairment associated with aging, and no drug treatment is presently available. In collaboration with the Institut de la Vision Biophytis develops a drug candidate (BIO201) based on norbixin, a di-apo-carotenoid, as IPI. We describe here the effects of norbixin on retinal pigmented epithelium (RPE) and retina photoprotection in vitro and in vivo.
The photo-protective effect of norbixin and of other carotenoids was evaluated on primary cultures of porcine RPE cells challenged with A2E and illuminated with blue light (N=16). In vivo experiments measured the photo-protective effect of norbixin one week after blue light damage in the Abca4-/-Rdh8-/- transgenic mouse model (which accumulates rapidly A2E in RPE cells). Twenty-eight 7-week-old mice were injected intra-vitreally in one eye with 120 mM norbixin (in 0.3% DMSO) or with DMSO alone, dark-adapted during 24 hours and exposed to blue light (4000 lux) for one hour. Ten mice were used as non-illuminated controls. Full field scotopic electroretinogram was measured one week after light damage and eyes were removed for histology and photoreceptor quantification. Bioavailability was tested in C57Bl/6 mice receiving norbixin 50 mg/kg per os (in oil/DMSO 9:1) or 5 mg/kg intraperitoneally (in DMSO/tetraglycol/water 1:2:7) (N=4). Norbixin was also assayed in a standard rat blue light model of photodamage by repeated intraperitoneal injections. For statistical analyses, one-way ANOVA followed by Dunnett’s tests were performed.
Norbixin showed an improved photo-protection to porcine RPE as compared with lutein or zeaxanthin. At 5 mM, norbixin protected 72.6% cells vs 36.2% and 32.3% for lutein and zeaxanthin, respectively. In vivo, norbixin significantly maintained the ERG a-wave (38% vs 15.9% for DMSO control; p<0.05) and b-wave (49% vs. 21% for DMSO control; p<0.01) after induction of light damage and protected 61% photoreceptors as compared to DMSO-injected eyes (32%; p<0.001). Norbixin had a good oral bioavailability (55%); it was recovered in the eyes, peaking at 40 ng/eye 30-60 min after oral intake and it was still detectable at 7 ng/eye after 24 hours. In the blue light rat model, norbixin was equally active as PBN, the positive control.
Norbixin appears promising for the development of an oral treatment of dry AMD, and the potential of BIO201 will be assessed in a forthcoming multicentric clinical trial.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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