Aging-US: Administration of the di-apocarotenoid norbixin is neuroprotective

09-08-2021

Aging-US published a Special Collection on Eye Disease which included "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" which reported that atrophic A\age-related macular degeneration and Stargardt disease are major blinding diseases affecting millions of patients worldwide - but no treatment is available.

Acute and chronic retinal degeneration following blue light damage in BALB/c mice and aging of Abca4-/- Rdh8-/- mice, respectively, reproduce features of AMD and STGD. Norbixin injected intraperitoneally in BALB/c mice, maintained scotopic and photopic electroretinogram amplitude and was neuroprotective.

Dr. Serge Camelo from The Sorbonne Université said, "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 is a major unmet medical need as it is estimated that more than 20 million patients will be affected by 2050 in the US alone. 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.

It has an autosomal recessive mode of inheritance and may lead to registered blindness within the second or third decade of life. It is formed by the reaction of 2 all-trans retinal molecules with phosphatidylethanolamine generating N-retinylidene-PE, as a detoxication mechanism of retinal isomers including all-trans and 11-cis-retinal.

Figure 6. Effect of norbixin late curative supplementation from 12 to 17 months in Abca4-/- Rdh8-/- mice. (A) Schematic representation of the 5-month late curative supplementation protocol design. (B) Scotopic A wave ERG recorded after 5 months of oral supplementation with norbixin in Abca4-/- Rdh8-/- mice compared to mice fed with normal chow (vehicle) and to 1.5- and 12-month-old mice. (C) Scotopic B wave. (D) Photopic B wave. (E) Quantification of photoreceptor nuclear layers along the superior and inferior poles of the retina each measured every 200 μm apart from the optic nerve. (F) A2E quantification in eyes from 12-month-old Abca4-/- Rdh8-/- mice, 17-month-old mice fed with normal chow or with norbixin-containing pellets. (G) Representative images of lipofuscin content in RPE cells of 17-month-old vehicle and norbixin-treated mice. Large granules of lipofuscin are found in the RPE cytoplasm (white asterisk). (H) Histograms showing the quantified lipofuscin granules expressed by area of 100 μm2. (I) Histograms representing the surface of cytoplasm occupied by lipofuscin and expressed in percentage of total cytoplasm surface. Bars represent mean ± s.e.m. with n = 8 per group (i.e. n=16 eyes per group for ERG). *p<0.05, **p<0.01 compared to vehicle (One-way ANOVA, Dunnett's post-test).

Under normal conditions the ABCA4 protein participates in the elimination of A2-PE from the photoreceptors and inhibition of this clearance increases the accumulation of A2E and all-trans-retinal dimer in the RPE. Recently, it has been shown that ABCA4 is also expressed in RPE cells where it would participate in the recycling of retinaldehyde released during proteolysis of rhodopsin in endolysosomes following phagocytosis of photoreceptor outer segments.

Indeed, it has been shown that as early as in 3-month-old Abca4-/- Rdh8-/- mice, the amplitudes of scotopic A and B waves and flicker ERG are reduced. Abca4-/- Rdh8-/- mice recapitulate most phenotypic retinal alterations observed during STGD and AMD, and represent a chronic model of these diseases.

Acute white-light exposure is known to induce apoptosis of photoreceptors in albino mice retinas.

Acute white-light exposure is known to induce apoptosis of photoreceptors in albino mice retinas

The Camelo Research Team concluded in their Aging-US Research Output, "our present study demonstrates that systemic administration of norbixin in the acute BLD model of dry AMD is neuroprotective and partially preserves photoreceptor function. In addition, 6 months of oral supplementation with norbixin is effective in Abca4-/-Rdh8-/- mice. We show that chronic norbixin supplementation reduces the concentration of A2E in the eye, that norbixin is neuroprotective, and preserves visual function of Abca4-/-Rdh8-/- mice, modelling retinal degenerative conditions such as STGD and dry AMD. We believe that treatment using norbixin could potentially preserve “night” and “day” visual acuity in humans affected by dry AMD and STGD. It is essential for patient care to develop drugs that are effective on visual function following oral administration rather than by repeated local intraocular injections. These results demonstrated the effectiveness of the norbixin in a chronic and acute model of retinal degeneration and could offer a new therapeutic strategy, alone or in combination with gene therapies, for AMD and/or STGD patients. Thus, norbixin is a good drug candidate to treat patients and may provide a cure for these very debilitating diseases."

Full Text - https://www.aging-us.com/article/103014/text

Correspondence to: Serge Camelo email: serge.camelo@biophytis.com

Keywords: norbixin, retinal function, A2E, AMD, Stargardt disease

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Cancer and aging are two sides of age-related tumorigenesis.

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