Eye movement recordings as an effectiveness indicator of gene therapy in RPE65-deficient canines: implications for the ocular motor system.
OBJECTIVE
To perform ocular motility recordings of infantile nystagmus (IN) in RPE65-deficient canines and determine whether they can be used as a motor indicator of restored retinal function to investigate the effects of gene therapy.


METHODS
Treated and untreated canines were comfortably suspended in a custom-built sling and encouraged to fixate on distant targets at gaze angles varying between +/-15 degrees horizontally and +/-10 degrees vertically. Ocular motility recordings were made, using two distinct methods-infrared reflection and high-speed video. The resultant recordings from three untreated, four treated, and three pre- and post-treatment dogs 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 and centralisation.


RESULTS
During fixation, the untreated dogs exhibited large-amplitude, classic IN waveforms, including pendular and jerk in both the horizontal and vertical planes, which prevented them from keeping the targets within the area centralis (the region of highest receptor density, spanning +/-3 degrees horizontally by +/-1.5 degrees vertically, analogous to the fovea). Some untreated dogs also had small-amplitude (0.5-1 degrees), high-frequency (6-9 Hz) oscillations. Under the same conditions, successfully treated canines no longer exhibited clinically detectable IN. Their IN was converted to waveforms with very low amplitudes that yielded higher NAFX values and allowed target images to remain well within the area centralis. Of note, uniocular treatment appeared to damp the IN in both eyes. Behaviorally, the treated dogs were able to successfully navigate through obstacles more easily without inadvertent contact, a task beyond the untreated dogs' ability.


CONCLUSIONS
Gene therapy that successfully restored retinal function also reduced the accompanying IN to such a great extent that it was not clinically detectable approximately 90% of the time in many of the dogs. IN improvement, as quantified by the NAFX, is an objective motor indicator of visual improvement due to gene therapy.
Jacobs
Jonathan B
JB
Daroff-Dell'Osso Ocular Motility Laboratory, Veterans Affairs Medical Center, Department of Neurology, Case Western Reserve University and University Hospital of Cleveland, OH 44106, USA.
Dell'Osso
Louis F
LF
Hertle
Richard W
RW
Acland
Gregory M
GM
Bennett
Jean
J
D000818:Animals; D001766:Blindness / Q000235:genetics / Q000503:physiopathology / Q000628:therapy / Q000662:veterinary*; D004283:Dog Diseases / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D004285:Dogs; D004584:Electronystagmography; D005133:Eye Movements / Q000502:physiology; D005136:Eye Proteins / Q000235:genetics*; D015316:Genetic Therapy; D020417:Nystagmus, Congenital / Q000503:physiopathology / Q000628:therapy / Q000662:veterinary*; D012162:Retinal Degeneration / Q000235:genetics / Q000503:physiopathology / Q000628:therapy / Q000662:veterinary*; D016896:Treatment Outcome
D005136:Eye Proteins