Jacobs Jonathan B, Dell'Osso Louis F, Wang Zhong I, Acland Gregory M, Bennett Jean
Daroff-Dell'Osso Ocular Motility Laboratory, Veterans Affairs Medical Center, Cleveland, OH 44106, USA.
Invest Ophthalmol Vis Sci. 2009 Oct;50(10):4685-92. doi: 10.1167/iovs.09-3387. Epub 2009 May 20.
To use ocular motility recordings to determine the changes over time of infantile nystagmus syndrome (INS) in RPE65-deficient canines with Leber Congenital Amaurosis (LCA) and assess the time course of the recalibration of the ocular motor system (OMS).
Nine dogs were treated bilaterally with AAV-RPE65. A second cohort of four dogs was treated with AAV2.RPE65, an optimized vector. Their fixation eye movements were recorded before treatment and at 4-week intervals for 3 months, by using high-speed (500 Hz) digital videography. The dogs were suspended in a sling and encouraged to fixate on distant (57 inches) targets at gaze angles varying between +/-15 degrees horizontally and +/-10 degrees vertically. The records for each eye were examined for qualitative changes in waveform and for quantitative changes in centralisation with the expanded nystagmus acuity function (NAFX) and compared with ERG results for restoration of receptor function.
First group: Before treatment, five of the dogs had clinically apparent INS with jerk, pendular, or both waveforms and with peak-to-peak amplitudes as great as 15 degrees . One dog had intermittent nystagmus. At the 1- and 2-month examinations, no change in nystagmus waveform or NAFX was observed in any of the initial dogs, while at 10 weeks, one dog treated bilaterally with the standard dosage showed reduced nystagmus in only one eye. The other eye did not respond to treatment, as confirmed by ERG. This result was unexpected since it was previously documented that unilateral treatment leads to bilateral reduction of INS. The other dog treated with the standard dosage showed no reduction of its small-amplitude, high-frequency pendular nystagmus despite positive ERG responses. Second group: Only one dog of the four had clinically detectable INS, similar in characteristics to that seen in the affected dogs of the first group. Unlike any previous dog studied, this one showed a damping of the nystagmus within the first 4 weeks after treatment.
In all but one of the cases in which OMS recalibration occurred, as measured by the clinical appearance of nystagmus and by quantitative measurement using the NAFX, the improvement was apparent no sooner than 10 weeks after treatment. Longer term, dose-related studies are needed to determine the minimum necessary degree of restored receptor functionality, the duration after rescue for recalibration of the OMS, and the conditions under which recalibration information can successfully affect the contralateral eye.
利用眼球运动记录来确定患有莱伯先天性黑蒙（LCA）的RPE65缺陷犬的婴儿型眼球震颤综合征（INS）随时间的变化，并评估眼球运动系统（OMS）重新校准的时间进程。
对9只犬进行双侧AAV-RPE65治疗。第二组4只犬接受了优化载体AAV2.RPE65的治疗。在治疗前以及治疗后3个月内每隔4周，通过高速（500Hz）数字摄像记录它们的注视眼动。将犬悬吊在吊带中，鼓励它们注视远处（57英寸）的目标，水平注视角度在±15度之间变化，垂直注视角度在±10度之间变化。检查每只眼睛的记录，观察波形的定性变化以及使用扩展的眼球震颤视力功能（NAFX）评估注视中心的定量变化，并与视网膜电图（ERG）结果进行比较，以评估受体功能的恢复情况。
第一组：治疗前，5只犬临床上表现出明显的INS，具有急跳、摆动或两种波形，峰峰值幅度高达15度。1只犬有间歇性眼球震颤。在1个月和2个月的检查中，最初的任何一只犬的眼球震颤波形或NAFX均未观察到变化，而在10周时，1只接受标准剂量双侧治疗的犬仅一只眼睛的眼球震颤有所减轻。视网膜电图证实，另一只眼睛对治疗无反应。这一结果出乎意料，因为之前有文献记载单侧治疗会导致INS双侧减轻。另一只接受标准剂量治疗的犬尽管视网膜电图反应呈阳性，但其小幅度、高频摆动性眼球震颤并未减轻。第二组：4只犬中只有1只临床上可检测到INS，其特征与第一组受影响的犬相似。与之前研究的任何犬不同，这只犬在治疗后的前4周内眼球震颤出现了衰减。
除1例之外，在所有通过眼球震颤的临床表现和使用NAFX进行定量测量来衡量OMS重新校准的病例中，改善在治疗后10周之前均未明显显现。需要进行更长期的、与剂量相关的研究，以确定恢复受体功能所需的最低必要程度、OMS重新校准在挽救后持续的时间，以及重新校准信息能够成功影响对侧眼的条件。
