Measures of Human Receptor and Post Receptor Activity

我们的长期目标是开发非侵入性技术来研究人类视网膜， 基础科学和临床目的。通过将当前的光传导理论应用于全场， 视网膜电图（ERG），我们成功地开发了广泛使用的技术，用于研究全球活动的 视杆细胞和视锥细胞以及视杆双极细胞。这些客观视网膜功能的指标是 用于全身给药药物治疗试验的适当结局指标。但不少 正在进行的和预期的涉及光感受器疾病的临床试验需要局部测量， 视网膜功能，如多焦视网膜电图（mfERG）、静态自动视野检查（SAP）和视杆细胞 和视锥介导的眼底跟踪视野检查，用于评价治疗效果。随着最近的事态发展， 通过视网膜成像，我们可以将视觉功能的局部测量与底层结构联系起来。我们有 聚焦于频域光学相干断层扫描（fdOCT）和眼底自发荧光（FAF）。这 工作，由目前的赠款支持，受益于我们的新的定量方法， 在fdOCT上看到的视网膜层厚度与其他结构和功能测量值的差异。即将到来的焦点将 用于患有遗传性视网膜变性（IRD）的患者，包括STGD 1， 突变。一个主要的目标是提供深入的病理生理学和进展率， 分子特征的患者与我们的新的成像和功能措施。 目前RP（主要是SAP和ERG）和STGD 1（主要是视力和 FAF）无法在相对较短的时间间隔内以适度的样本量评估变化， 导致昂贵和冗长的临床试验。我们最近的工作与恩面板OCT代表了一个激进的 RP和STGD 1的翻译研究的变化。我们在RP的工作实际上是独一无二的，在我们的步骤， 建立定量OCT作为可行的临床试验结局指标。如NEI-FDA所示， 终点研讨会（NIH，2016年11月9日），对“解剖学”终点有相当大的热情， IRD。尽管如此，要将措施扩大到经济区，并建立 外部视网膜结构改变（即EZ区域）与功能丧失之间的关系。计划中的实验 将通过开发和评估新的表面活性剂来确定受体丢失的程度、性质和进展。 用于量化宽场OCT扫描上的受体区域的平板方法，将OCT参数与杆相关联 和锥SAP，开发模型相关杆和锥的敏感性，以定量措施的内部和外部 节段长度、外核层厚度和内核层厚度，并使用多模式成像 方法包括OCT、红外（IR）反射率和FAF，以检验有关疾病机制的假设， 疾病进展的模型。注意，这些实验同样适用于RP和STGD 1。采取 总之，这些研究继续支持临床试验的新的和更有效的结果测量。

Our long-term objective has been to develop noninvasive techniques for studying the human retina for both basic science and clinical purposes. By applying current theories of phototransduction to the full-field electroretinogram (ERG), we successfully developed widely used techniques for studying the global activity of the rod and cone receptors, as well as the rod bipolar cells. These indices of objective retinal function are appropriate outcome measures for treatment trials with systemically administered agents. However, many ongoing and anticipated clinical trials involving diseases of the photoreceptors require localized measures of retinal function, such as the multifocal electroretinogram (mfERG), static automated perimetry (SAP), and rod and cone-mediated fundus tracking perimetry, for evaluating treatment efficacy. With recent developments in retinal imaging, we can relate localized measures of visual function to the underlying structure. We have focused on frequency domain optical coherence tomography (fdOCT) and fundus autofluorescence (FAF). This work, supported by the current grant, has benefitted from our novel quantitative approaches for relating the thickness of retinal layers seen on fdOCT to other structural and functional measures. The upcoming focus will be on patients having Inherited Retinal Degenerations (IRDs), including STGD1, with identified genetic mutations. A primary goal is to provide insights into the pathophysiology and rates of progression in molecularly characterized patients with our novel imaging and functional measures. Present outcome measures in RP (primarily SAP and ERGs), and STGD1 (primarily visual acuity and FAF) are incapable of assessing change with modest sample sizes over a relatively short time interval, resulting in expensive and lengthy clinical trials. Our recent work with en face slab OCT represents a radical change in translational research in RP and STGD1. Our work in RP is virtually unique in the steps we are taking to establish quantitative OCT as a viable clinical trial outcome measure. As evidenced at the NEI-FDA endpoints workshop (NIH, Nov 9, 2016), there is considerable enthusiasm for an “anatomical” endpoint for IRDs. Nevertheless, there is still much to be done to expand the measures to EZ area and to establish the relationship between outer retinal structural alterations (i.e. EZ area) and functional loss. Planned experiments will determine the extent, nature and progression of receptor loss by developing and evaluating novel en face slab methods for quantifying the receptor regions on wide-field OCT scans, relating OCT parameters to rod and cone SAP, developing models relating rod and cone sensitivity to quantitative measures of inner and outer segment length, outer nuclear layer thickness, and inner nuclear layer thickness, and using multimodal imaging methods including OCT, infrared (IR) reflectance and FAF to test hypotheses about disease mechanisms and models of disease progression. Note that these experiments apply equally to RP and to STGD1. Taken together, these studies continue to support novel and more efficient outcome measures for clinical trials.