Structure-Function Relationships in Stargardt Disease.

项目总结/摘要 ABCA 4基因相关性Stargardt病（STGD 1）是最常见的青少年黄斑变性， 营养不良，可影响儿童和成人。它是一种常染色体隐性遗传性状 与ABCA 4基因突变有关。患者经历缓慢的渐进性视力丧失 功能，特别是中央视觉，并可在几十年内达到法律的失明。目前没有 STGD 1的治疗方法潜在的治疗选择包括药物，基因替代 和干细胞移植方法。未来STGD 1治疗试验的成功将取决于 适当选择试验终点。监管机构更喜欢视觉功能结果， 然而，对于STGD 1试验可能是无效的，因为在STGD 1试验中， 疾病自然史眼底自发荧光法测量视网膜结构参数 和光学相干断层扫描（OCT）成像在临床上广泛用于跟踪疾病 进展但是，在接受SP作为试验终点之前，监管机构需要证据 SP和功能结局之间的显著关系，包括横截面 结构变化和“未来临床”之间的关系以及纵向关联 重大成果”。这种证据（或缺乏）尚未在STGD 1中得到充分证明。的 继发于Stargardt病的萎缩进展（ProgStar）前瞻性研究，包括其 Stargardt病视杆功能的辅助暗视微视野评估（SMART）研究， 一项针对259名经分子学证实的STGD 1患者的多中心国际研究， 随访2年以上的历史数据。利用这些研究的数据，我们的目标是：首先， 评估FAF衍生参数与萎缩性病变大小的横截面和纵向相关性 最佳矫正视力（BCVA）和明视黄斑敏感度的功能结局 和暗视微视野检查。第二，评估以下方面的横截面和纵向关联： OCT导出的视网膜完整性参数，包括内部和外部的厚度和完整区域， 视网膜外层，具有BCVA以及明视和暗视黄斑敏感性的功能结果。 将使用具有广义估计方程的广义线性模型。所学知识 将展示FAF和OCT衍生的SP，在什么程度上，以及在什么表型下 条件，与视觉功能的丧失，从而导致更好地了解 疾病病理生理学这些知识将为终点和入组标准的选择提供信息， 即将进行的STGD 1治疗试验。

Project Summary/Abstract ABCA4 gene related Stargardt disease (STGD1) is the most common juvenile macular dystrophy and can affect both children and adults. It is inherited as an autosomal-recessive trait associated with mutations in the ABCA4 gene. Patients experience a slow progressive loss of visual function, especially central vision, and can reach legal blindness in decades. Currently there is no approved treatment for STGD1. Potential treatment options include pharmacologic, gene replacement and stem-cell transplantation approaches. Success of future STGD1 treatment trials will depend on appropriately selected trial endpoints. Regulatory agencies prefer visual function outcomes which however can be inefficient for STGD1 trials because of the slow rates of visual function loss in the disease natural history. Retinal structural parameters (SP) measured by fundus autofluorescence (FAF) and optical coherence tomography (OCT) imaging are widely used clinically to track disease progression. However, before accepting an SP as a trial endpoint, regulatory agencies require evidence of significant relationships between the SP and functional outcomes, including both cross-sectional relationships and also longitudinal associations between structural changes and “a future clinically significant outcome”. Such evidence (or lack of) has not been well demonstrated for STGD1. The Progression of Atrophy Secondary to Stargardt Disease (ProgStar) prospective study, including its ancillary Scotopic Microperimetric Assessment of Rod Function in Stargardt Disease (SMART) study, is a multi-center international study of 259 molecularly confirmed STGD1 patients to generate natural history data over 2 years of follow-up. Leveraging data from these studies, our aims are: First, to assess cross-sectional and longitudinal associations of FAF derived parameters on atrophic lesion size with functional outcomes of best corrected visual acuity (BCVA) and macula sensitivities from photopic and scotopic microperimetry tests. Second, to assess cross-sectional and longitudinal associations of OCT derived parameters on retinal integrity, including thicknesses and intact areas of the inner and outer retinal layers, with functional outcomes of BCVA and photopic and scotopic macula sensitivities. Generalized linear models with generalized estimating equation will be used. The knowledge learned will demonstrate what FAF and OCT derived SPs, at what magnitudes, and under what phenotypic conditions, are associated with loss of visual functions, thus leading to a better understanding of the disease pathophysiology. The knowledge will inform choices of endpoints and enrollment criteria for forthcoming STGD1 treatment trials.