Barrier free chromatic pupillometry in children from infancy on. A novel biomarker to quantify outer and inner retinal function in inherited retinal disorders as a measure of therapeutic benefit after gene therapy.

视网膜基因添加疗法已经并正在进一步开发用于几种潜在的致盲性视网膜营养不良。对于RPE 65缺乏症，预计FDA和EMA将很快批准一种药物。由于目前的治疗成功率仍然有限，而且由于具有足够高灵敏度的功能评估方法有限，因此治疗益处难以量化。提高治疗成功率的一种方法可能是尽可能少地治疗退化的视网膜。这可能意味着非常年轻的患者甚至婴儿和幼儿将在未来被考虑接受治疗。由于能力和依从性有限，因此需要新的客观的功能和形态学指标，我们的目标是开发高度可靠的生物标志物，从婴儿期开始的遗传性视网膜营养不良的视网膜功能，并将它们与视网膜形态学相关联。我们将开发，构建和测试一个全新的概念，客观评估视网膜功能。所提出的无接触和无障碍的彩色瞳孔测量方法能够单独刺激一只眼睛或同时刺激两只眼睛并同时记录瞳孔。它包括一个专门的远程眼动跟踪器，用于在线测量瞳孔直径，同时测量眼睛注视和头部位置，这是纠正瞳孔变形引起的伪影所必需的。受试者通过基于LED的显示器使用具有不同背景和强度的蓝光和红光进行刺激，所有这些都不需要固定头部位置。这将允许视杆细胞、视锥细胞和ipRPGC介导的瞳孔收缩的年龄无关性评价作为其功能的指标。这在LCA类型的IRD中特别重要，其中早期视杆和/或视锥功能低于Ganzfeld视网膜电图的检测水平。将用无障碍彩色瞳孔测量法评估的视杆、视锥和ipRGC功能与用手持式OCT评估的中央视网膜的形态学数据相关联，并用DIOCTA软件进行分析。无障碍瞳孔测量获得的值将与我们以前开发的双眼彩色瞳孔测量能够执行这两种方法的年龄较大的儿童进行验证。

Retinal gene addition therapy has been and is further developed for several potentially blinding retinal dystrophies. For RPE65 deficiency a drug is expected to be soon approved by the FDA and EMA. Treatment benefit has been difficult to quantify due to still limited treatment success today, but also because of limited functional assessment methods with high enough sensitivity. One way to improve treatment success may be to treat as little degenerated retina as possible. This may mean that very young patients or even infants and toddlers will be considered for treatment in the future. Due to limited capacity and compliance new objective measures of function and morphology are therefore needed.Our aim is to develop highly reliable biomarkers of retinal function in inherited retinal dystrophies from infancy on and to correlate them with retinal morphology. We will develop, construct and test an entirely new concept of objective assessment of retinal function. The proposed method of contact- and barrier-free chromatic pupillometry enables separate stimulation of one eye or stimulation of both eyes at the same time and simultaneous recording of the pupils. It consists of a specialized remote eye-tracker to measure online pupil diameter and at the same time eye gaze and head position, necessary to correct pupil deformation induced artifacts. The subject is stimulated through an LED-based monitor using blue and red light with different backgrounds and intensities, all this without the need to fix head position. This will allow age-independent evaluation of rod, cone, and ipRPGCs mediated pupillary constriction as an indicator of their function. This is particularly important in IRDs of the LCA type where early on rod and/or cone function are below detection level with Ganzfeld electroretinography. Rod, cone, and ipRGC function as assessed with barrier-free chromatic pupillometry will be correlated to morphological data of the central retina, assessed with hand-held OCT, and analyzed with DIOCTA software. Values obtained with barrier-free pupillometry will be validated with our previously developed binocular chromatic pupillometry in older children capable of performing both methods.