Gene Therapy to Abolish Congenital Nystagmus in RPE65-Deficient Canines

Abstract

Abstract: : Purpose: To perform ocular motility recording of congenital nystagmus (CN) in RPE65-deficient canines and determine if they can be used as an indicator of restored retinal function to investigate the effects of gene therapy. Methods: Treated (n=3) and untreated (n=4) dogs were comfortably suspended in a custom-built sling and encouraged to fixate on distant (145 cm) targets at gaze angles varying between ±15°, horizontally, and ±10° vertically. Teller Acuity Testing (TAT) was performed as a separate measure of visual acuity. Ocular motility recordings were made, using two distinct methods—infrared reflection and high-speed video—during the fixation of the targets and TAT cards. The resulting recordings were analyzed for using the eXpanded Nystagmus Acuity Function (NAFX), which yields an objective assessment of best potential visual acuity, based on the duration and repeatable accuracy of foveation/centralisation. Results: During fixation, the untreated canines exhibited large-amplitude classical CN waveforms, including pendular and jerk, in both the horizontal and vertical planes that prevented them from keeping the targets within the area centralis (the region of highest receptor density, spanning ±3° horizontally by ±1.5° vertically, analogous to the fovea). Some untreated dogs also had a small-amplitude (0.5-1°), high-frequency (6-9 Hz) oscillations. Under the same conditions, successfully treated canines exhibited no clinically detectable CN but rather, CN whose very low amplitudes yielded higher NAFXs, and allowed target images to remain well within the area centralis. Interestingly, uniocular treatment damped the CN in both eyes. Conclusions: Gene therapy that successfully restored retinal function also reduced the accompanying CN to such a great extent (~90%) as to be considered clinically abolished.

Keywords: nystagmus • gene transfer/gene therapy • animal model