**Vitamin A Derivatives as Treatment Options for Retinal Degenerative Diseases**

#### **Lindsay Perusek and Tadao Maeda**

**Abstract:** The visual cycle is a sequential enzymatic reaction for vitamin A, all-*trans*-retinol, occurring in the outer layer of the human retina and is essential for the maintenance of vision. The central source of retinol is derived from dietary intake of both retinol and pro-vitamin A carotenoids. A series of enzymatic reactions, located in both the photoreceptor outer segment and the retinal pigment epithelium, transform retinol into the visual chromophore 11-*cis*-retinal, regenerating visual pigments. Retina specific proteins carry out the majority of the visual cycle, and any significant interruption in this sequence of reactions is capable of causing varying degrees of blindness. Among these important proteins are Lecithin:retinol acyltransferase (LRAT) and retinal pigment epithelium-specific 65-kDa protein (RPE65) known to be responsible for esterification of retinol to all-*trans*-retinyl esters and isomerization of these esters to 11-*cis*-retinal, respectively. Deleterious mutations in these genes are identified in human retinal diseases that cause blindness, such as Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). Herein, we discuss the pathology of 11-*cis*-retinal deficiency caused by these mutations in both animal disease models and human patients. We also review novel therapeutic strategies employing artificial visual chromophore 9-*cis*-retinoids which have been employed in clinical trials involving LCA patients.

Reprinted from *Nutrients*. Cite as: Perusek, L.; Maeda, T. Vitamin A Derivatives as Treatment Options for Retinal Degenerative Diseases. *Nutrients* **2013**, *5*, 2646-2666.

### **1. Introduction**

Vitamin A is an essential vitamin for vertebrates and therefore must be obtained from dietary sources. Intake of adequate vitamin A is required in adults to maintain immune system integrity, vision, and the regulation of gene transcription, while in embryo development it is required for organogenesis, tissue differentiation and hematopoiesis [1–3]. Total vitamin A intake consists of many dietary forms including retinyl esters, ȕ-carotene and free retinol. The various ingested forms of vitamin A are then processed, stored in the liver and can be released into the systemic circulation upon demand.

The various functions of vitamin A are carried out by several metabolically active derivatives including 11-*cis*-retinal and all-*trans*-retinoic acid, which are required for vision and transcriptional gene regulation respectively [4,5]. Enzymatic activity and gene regulation within many tissues is dependent upon a consistent supply of vitamin A, therefore tissues such as the eye, possess cyclic series of reactions to regenerate biologically active vitamin A such as a visual chromophore 11-*cis*-retinal. The efficient renewal of vitamin A is termed the visual cycle, and is indispensable for normal vision in humans. Genetic mutations which result in faulty enzymes required for the eye specific processing of vitamin A may cause early onset retinal degeneration due to the lack of 11-*cis*-retinal chromophore and ultimately can lead to complete loss of vision. Retinoid therapies utilize specific isomers of vitamin A and have proven to be effective at alleviating progressive tissue damage in animal models of retinal degeneration. Retinoid treatment maintains functional responses as well as tissue integrity both of which are observed to decline significantly with age in animal models of retinal diseases. Similar phenotypic pathology and age related degeneration trends are seen in human patients suffering from blinding diseases such as Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). Retinoid therapies therefore have the potential to improve the quality of life in patients suffering from genetic retinal diseases by delaying progressive vision loss.
