Evaluation Of The Success Of Gene Therapy In The Older RPE65-deficient Dog

Abstract

Purpose: : Gene therapy for RPE65 deficiency has shown success in dogs, mice and humans. Most of the initial canine trials were performed on young RPE65-deficient dogs, generally with remarkable success. Affected dogs have a slow but progressive degeneration of photoreceptors suggesting success of treatment is likely to decrease with age. Previously published results reported variable success in dogs older than 2 years of age. The aim of this study was to evaluate the success of gene therapy in RPE65-deficient dogs over 2 years of age.

Methods: : 12 eyes of 8 RPE65-deficient dogs aged 2 to 5.3 years underwent subretinal injection of an AAV2/2 -hRPE65p-hRPE65 construct. ERG and vision testing were performed prior to treatment and 2 and 4 months after treatment.

Results: : In all 12 eyes there was an improvement in dim light vision. Dark-adapted ERGs were assessed at 1 cdS/m², an intensity at which untreated eyes had no response. 7 of 12 eyes developed a robust ERG response at this intensity, while 4 eyes had a very low amplitude response and one eye did not have a recordable response at this intensity. Cone function was assessed by 33Hz flicker. 7 of 12 eyes had good improvement in amplitudes and a further 2 eyes had marginal improvement. Of the 5 eyes with poor ERG responses this could be explained in 2 eyes by a small injection bleb and in a further 2 eyes by the development of ophthalmoscopic evidence of patchy areas of retinal degeneration in the injected area. However in 1 eye (of a 5.2 year old dog) there was a large injection bleb with no obvious complications but no ERG improvement by these measures.

Conclusions: : Improvement in retinal function by gene therapy in the RPE65-deficient dog is possible to at least 5 years of age. Area of injection and development of patchy retinal degeneration in the treated areas appeared to be limiting factors for successful outcome as assessed by ERG. Demonstrable improvement in dim light vision was present in all treated eyes including one in which there was not a convincing improvement in ERG function.

Keywords: gene transfer/gene therapy • retinal degenerations: hereditary • electroretinography: non-clinical