A Comprehensive Study of the Retinal Phenotype of Rpe65-Deficient Dogs.

Matthew J Annear,Simon M Petersen-Jones,Paul G Curran,Laurence M Occelli,Robin R Ali,Alexander J Smith,Freya M Mowat,James W Bainbridge

doi:10.3390/cells10010115

Abstract

The Rpe65-deficient dog has been important for development of translational therapies of Leber congenital amaurosis type 2 (LCA2). The purpose of this study was to provide a comprehensive report of the natural history of retinal changes in this dog model. Rpe65-deficient dogs from 2 months to 10 years of age were assessed by fundus imaging, electroretinography (ERG) and vision testing (VT). Changes in retinal layer thickness were assessed by optical coherence tomography and on plastic retinal sections. ERG showed marked loss of retinal sensitivity, with amplitudes declining with age. Retinal thinning initially developed in the area centralis, with a slower thinning of the outer retina in other areas starting with the inferior retina. VT showed that dogs of all ages performed well in bright light, while at lower light levels they were blind. Retinal pigment epithelial (RPE) inclusions developed and in younger dogs and increased in size with age. The loss of photoreceptors was mirrored by a decline in ERG amplitudes. The slow degeneration meant that sufficient photoreceptors, albeit very desensitized, remained to allow for residual bright light vision in older dogs. This study shows the natural history of the Rpe65-deficient dog model of LCA2.

Highlights

Mutations in the Rpe65 gene cause early-onset retinal dystrophies in dogs [1], mice [2,3,4]and humans [5]
Rpe65 is an isomerase expressed in the retinal pigment epithelium (RPE), where it converts alltrans retinyl esters to 11-cis retinol
Residual rod photoreceptor function may result from opsins combining with other retinyl esters such as 9-cis retinal that are present at low levels [9]; and in the case of cones, an additional pathway independent of Rpe65 may allow for some cone chromophore production [10]

Summary

Introduction

Mutations in the Rpe gene cause early-onset retinal dystrophies in dogs [1], mice [2,3,4]and humans [5]. Residual rod photoreceptor function may result from opsins combining with other retinyl esters such as 9-cis retinal that are present at low levels [9]; and in the case of cones, an additional pathway independent of Rpe may allow for some cone chromophore production [10]. Any such alternative pathway is insufficient to provide normal cone function in the absence of Rpe65 [11]. An important feature of Rpe retinopathy is that there is an initial preservation of retinal structure, despite loss of function; a feature that made this dystrophy attractive for gene augmentation therapy (reviewed in [12])

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