Diseases Caused by Defects in the Visual Cycle: Retinoids as Potential Therapeutic Agents

Abstract

Absorption of a photon by an opsin pigment causes isomerization of the chromophore from 11-cisretinaldehyde to all-trans-retinaldehyde. Regeneration of visual chromophore following light exposure is dependent on an enzyme pathway called the retinoid or visual cycle. Our understanding of this pathway has been greatly facilitated by the identification of disease-causing mutations in the genes coding for visual cycle enzymes. Defects in nearly every step of this pathway are responsible for human-inherited retinal dystrophies. These retinal dystrophies can be divided into two etiologic groups. One involves the impaired synthesis of visual chromophore. The second involves accumulation of cytotoxic products derived from all-trans-retinaldehyde. Gene therapy has been successfully used in animal models of these diseases to rescue the function of enzymes involved in chromophore regeneration, restoring vision. Dystrophies resulting from impaired chromophore synthesis can also be treated by supplementation with a chromophore analog. Dystrophies resulting from the accumulation of toxic pigments can be treated pharmacologically by inhibiting the visual cycle, or limiting the supply of vitamin A to the eyes. Recent progress in both areas provides hope that multiple inherited retinal diseases will soon be treated by pharmaceutical intervention.

Light damage to the retina: an historical approach

“…Patients suffering from diseases affecting the visual cycle, such as Stargardt's dystrophy, Best disease, or Oguchi disease, should require extra care as they might suffer increased susceptibility to light damage, as was found in animal models. 7,32 Continued research on photochemical damage is relevant because many open questions remain, only some of them treated in this limited review. An action spectrum for freely moving animals exposed to continuous light for one or more natural days, thus in the 'Noell conditions', is still lacking, and the search for the photosensitizers underlying the Ham-type action spectrum is far from complete.…”

Phototransduction and retinal degeneration in Drosophila

“…In Drosophila, defects in the generation of the chromophore cause profound reductions in opsin levels [71], while this is not the case in vertebrate rods and cones [72]. It has been suggested that the chromophore accelerates opsin maturation by facilitating deglycosylation and transport of the opsin [73,74].…”

“…Vitamin A (all-trans retinol) is subsequently transported to the retinal pigment cells where it is converted to the chromophore through a process dependent on the PINTA retinoid-binding protein and the NINAG oxidoreductase. The chromophore is transported to the photoreceptor cells where it binds to the opsin resulting in the generation of rhodopsin pigment epithelium (RPE) [72], it appears that Drosophila retinal pigment cells are the closest functional equivalent to the RPE. The ninaG gene encodes an oxidoreductase, which is proposed to act in the conversion of (3R)-3hydroxyretinol to the 3S enantiomer in the compound eye [82,83].…”

Autophagy supports survival and phototransduction protein levels in rod photoreceptors

“…Disease is typically associated with the production of harmful gene products that promote pathology by inhibiting critical pathways resulting in cell death. [24][25][26] Strategies to prevent photoreceptor death during retinal degenerative disease such as gene replacement therapies or inhibition of cell death pathways have been undertaken with some success; [27][28][29] however, effective treatments for these blinding disorders are lacking.…”