Prolonged prevention of retinal degeneration with retinylamine loaded nanoparticles

Abstract

Retinal degeneration impairs the vision of millions in all age groups worldwide. Increasing evidence suggests that the etiology of many retinal degenerative diseases is associated with impairment in biochemical reactions involved in the visual cycle, a metabolic pathway responsible for regeneration of the visual chromophore (11-cis-retinal). Inefficient clearance of toxic retinoid metabolites, especially all-trans-retinal, is considered responsible for photoreceptor cytotoxicity. Primary amines, including retinylamine, are effective in lowing the concentration of all-trans-retinal within the retina and thus prevent retina degeneration in mouse models of human retinopathies. Here we achieved prolonged prevention of retinal degeneration by controlled delivery of retinylamine to the eye from polylactic acid nanoparticles in Abca4−/−Rdh8−/− (DKO) mice, an animal model of Stargardt disease/age-related macular degeneration. Subcutaneous administration of the nanoparticles containing retinylamine provided a constant supply of the drug to the eye for about a week and resulted in effective prolonged prevention of light-induced retinal degeneration in DKO mice. Retinylamine nanoparticles hold promise for prolonged prophylactic treatment of human retinal degenerative diseases, including Stargardt disease and age-related macular degeneration.

Norbixin Protects Retinal Pigmented Epithelium Cells and Photoreceptors against A2E-Mediated Phototoxicity In Vitro and In Vivo

“…All- trans -retinal accumulation activates the proapoptotic factor Bax and evokes retinal cell death [74]. Light-induced (10,000 lux for 1 hour) retinal degeneration in this model demonstrated the efficacy of drugs such as retinylamine or emixustat [52,75,76]. By contrast, this treatment induced no retinal degeneration and only a slight ERG loss in Abca4 +/+ Rdh8 +/+ Rpe65-Leu450 and rd8 background mice.…”

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

“…This suggests that a sharp reduction of A2E concentration is necessary to protect cone photoreceptor function, whereas a more limited reduction of A2E concentration appears to be sufficient to protect rod photoreceptor function. Other compounds including retinylamine [36,53], C20-d3vitamin A, [54], Emixustat [55], primary amines [56], omega-3 fatty acids [57] and the selective oestrogen receptor modulator raloxifene [47], among others, have been shown to reduce A2E accumulation and concomitantly to "rescue" retinal degeneration in Abca4 -/-Rdh8 -/mice or Abca4 -/in vivo. Altogether, this supports the hypothesis that norbixin effectiveness is at least partly linked to the level of reduction of ocular A2E concentration.…”

Retinylamine Benefits Early Diabetic Retinopathy in Mice

“…N-Retinylamides are the dominant form of the drug that accumulates in RPE. Their levels build up within 2 h after intraperitoneal injection of Ret-NH 2 to reach ϳ100 pmol/eye after which their levels slowly decline over the next 7-10 days, reaching a relatively low but stable level of 2-4 pmol/eye (19,21,28,29). Lrat Ϫ/Ϫ mice are chromophore-deficient, and consequently their rod and cone visual functions are severely attenuated at an early age (30).…”