In vitro and in vivo characterization of BIO203, a new amide norbixin conjugate with improved pharmacokinetic profile. Potential for oral treatment of age‐related retinal degeneration

Abstract

AbstractPurpose: We have previously shown that 9′‐cis‐norbixin (norbixin) protects retinal pigmented epithelium (RPE) cells against phototoxicity induced by blue light and N‐retinylidene‐N‐retinylethanolamine (A2E) in vitro and preserves visual function in animal models of dry Age‐related Macular Degeneration (AMD) in vivo. The purpose of this study was to examine the mode of action and the in vitro and in vivo effects of CN30, a norbixin monoamide conjugate.Methods: Ocular pharmacokinetics in rats administered orally with 50 mg/kg of norbixin, or its conjugate (CN30) were compared. Their effect on photoprotection of primary porcine RPE cells challenged with A2E and blue‐light illumination was quantified. The effects of CN30 on the A2E‐induced transactivation of PPARs, AP‐1 and NF‐κB were measured by reporter gene luciferase activity. The expression of IL‐6, IL‐8, and VEGF was measured by RT‐QPCR. The in vivo neuroprotective effect of intraperitoneally administered CN30 was evaluated by measuring retinal thickness and electroretinogram (ERG) amplitudes in a blue‐light damage (BLD) acute model in albino rats. CN30 efficacy was also assessed by ERG after 6 months oral supplementation in Abca4−/− Rdh8−/− mice.Results: Compared to norbixin, CN30 displays improved stability and enhanced ocular maximal concentration and exposure (AUC). Similar to our previous observation with norbixin, CN30 mode of action involves the inhibition of PPARs, NF‐κB and AP‐1 transactivation. CN30 reduces IL‐6, IL‐8 and VEGF expression induced by A2E in vitro. In vivo, CN30 protects visual function and retinal structure in albino rats subjected to BLD in an acute model of retinal degeneration. Moreover, 6 months oral supplementation also improve visual function in a model of dry AMD: the Abca4−/− Rdh8−/− double knock‐out mice.Conclusions: CN30 retains the protective properties of norbixin in vitro and in vivo, and displays improved stability and pharmacokinetic properties. This could open new avenues for the oral treatment of retinal degenerative diseases such as dry AMD.