MEASURES OF HUMAN RECEPTOR AND POST RECEPTOR ACTIVITY

描述(申请人提供)：我们的长期目标是开发一套研究人类视网膜的非侵入性技术。通过将光转导的新技术和现有理论应用于全场视网膜电信号(ERG)，我们成功地发展了广泛使用的非侵入性技术来研究视杆细胞和视锥细胞以及视杆双极细胞的整体活动。这些客观的视网膜功能指标可以作为系统给药治疗试验的适当结果指标。然而，许多正在进行的和预期的涉及受体疾病的临床试验需要视网膜功能的局部测量，如多焦ERG和静态自动视野检查，以评估治疗效果。然而，这些测试很难进行，耗时长，而且对患者不友好，而且通常只评估锥体功能。由于视网膜成像的最新发展，我们现在可以直接将这些功能测量与潜在结构联系起来。我们一直致力于一种新的非侵入性测量视网膜结构(解剖)的技术--频域光学相干断层扫描(FdOCT)。这项工作得到了目前拨款的支持，得益于我们评估fdOCT扫描上所见的视网膜层分割的新的定量方法。作为目标1的一部分，我们评估和改进了我们的疾病相关的光感受器损伤的fdOCT措施，并在临床上测试了这些措施的有效性。这包括开发和评估量化fdOCT扫描的新方法。我们使用这些方法来检验关于疾病机制的假设，以及疾病进展的模型。此外，我们建议检验这样一种假设，即特定的fdOCT测量(即IS/OS等高线)可以提供比目前视网膜色素变性(RP)等疾病的标准测量更好的疾病进展测量。作为目标2的一部分，我们将我们的方法扩展到黄斑疾病，这是对正常视觉功能最重要的区域。基于黄斑疾病可能首先影响视杆的证据，我们试图确定早期老年性黄斑变性(AMD)、地理萎缩和Stargardt病患者视杆功能的眼底周长测量与受体完整性的fdOCT测量之间的关系。我们将验证这样一种假设，即视杆状眼底视野检查和fdOCT对这些疾病的进展比视力或眼底照相上萎缩面积的测量更敏感。目前RP和黄斑部疾病进展的功能测量的内在变异性对开发有效治疗方法的努力是一个实质性的威慑。由于需要大量患者和长时间的试验，成本变得令人望而却步。确定fdOCT在RP中的实用性和有效性，以及它与黄斑疾病局部视杆和视锥介导功能的测量之间的关系，可以深刻地提高未来临床试验在这些疾病中的可行性。

DESCRIPTION (provided by applicant): Our long-term objective has been to develop a set of noninvasive techniques for studying the human retina. By applying novel techniques and current theories of phototransduction to the full-field electroretinogram (ERG), we have successfully developed widely-used noninvasive 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 can be appropriate outcome measures for treatment trials with systemically-administered agents. However, many ongoing and anticipated clinical trials involving diseases of the receptors require localized measures of retinal function, such as the multifocal ERG and static automated perimetry, for evaluating treatment efficacy. These tests, however, are difficult to administer, time consuming, and not patient friendly, plus, as typically used, assess only cone function. Due to recent developments in retinal imaging, we can now relate these functional measures directly to underlying structure. We have been focusing our efforts on a new noninvasive technique for measuring the structure (anatomy) of the retina, frequency domain optical coherence tomography (fdOCT). This work, supported by the current grant, has benefitted from our novel quantitative approaches to assessing segmentation of retinal layers seen on fdOCT scans. As part of Aim 1, we evaluate and improve our fdOCT measures of disease related damage to the photoreceptors and test the efficacy of these measures in the clinic. This includes developing and evaluating new methods for quantifying fdOCT scans. We use these methods to test hypotheses about disease mechanisms, as well as models of disease progression. In addition, we propose to test the hypothesis that a particular fdOCT measure (i.e. the IS/OS contour) can provide a better measure of disease progression than current standard measures for diseases such as retinitis pigmentosa (RP). As part of Aim 2, we extend our approach to diseases of the macula, the region of greatest importance to normal visual function. Motivated by evidence that diseases of the macula may affect the rods first, we seek to determine the relationship between fundus perimetric measures of rod function and fdOCT measures of receptor integrity in patients with early age-related macular degeneration (AMD), geographic atrophy, and Stargardt disease. We will test the hypothesis that rod fundus perimetry and fdOCT are more sensitive to progression in these diseases than visual acuity or measures of the area of atrophy on fundus photography. The inherent variability in current functional measures of progression in RP and diseases of the macula is a substantial deterrent to efforts to develop effective treatments. Costs become prohibitive due to the large numbers of patients and extensive trial durations that are required. Determining the utility and validity of fdOCT in RP, and its relationship to measures of local rod- and cone-mediated function in macular disease, could profoundly enhance the feasibility of future clinical trials in these diseases.