Abstract
Purpose :
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.
Methods :
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.
Results :
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.
Conclusions :
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.