Structure-Function Relationships in Stargardt Disease.

项目摘要/摘要 ABCA4基因相关的Stargardt病(STGD1)是最常见的青少年黄斑 营养不良，对儿童和成人都有影响。它是一种常染色体隐性遗传性状 与ABCA4基因突变有关。患者经历了缓慢进行性的视力丧失 功能，特别是中央视力，可在几十年内达到法律盲目。目前没有 批准对STGD1进行治疗。潜在的治疗选择包括药物、基因替代 以及干细胞移植的方法。未来的STGD1治疗试验的成功将取决于 选择适当的试验终点。监管机构更喜欢视觉功能结果 然而，对于STGD1试验来说，由于视觉功能丧失的速度很慢，所以效率可能不高 疾病自然病史。眼底自体荧光法测量视网膜结构参数(SP) 和光学相干层析成像(OCT)成像被广泛用于临床跟踪疾病 进步。但是，在接受SP作为试验终点之前，监管机构需要证据 SP和功能结果之间的显著关系，包括横断面 结构变化和临床上的未来之间的关系和纵向联系 重大成果“。这样的证据(或缺乏)对于STGD1来说并没有得到很好的证明。这个 Stargardt病继发萎缩(ProgStar)前瞻性研究进展，包括ITS Stargardt病(SMART)研究中视杆功能的辅助暗视微视野评估 一项对259名分子证实的STGD1患者进行的多中心国际研究 2年以上随访病史资料。利用这些研究的数据，我们的目标是：第一， 评估Faf衍生参数与萎缩性病变大小的横断面和纵向相关性 最佳矫正视力(BCVA)和明视黄斑敏感度的功能结果 以及暗视微视野检查。第二，评估横截面和纵向关联 OCT得到的关于视网膜完整性的参数，包括视网膜内和视网膜的厚度和完好区 视网膜外层，具有BCVA和明、暗视黄斑敏感度的功能结果。 将使用带有广义估计方程的广义线性模型。学到的知识 将展示什么是FAF和OCT派生的SP，在什么程度上，在什么表型下 情况与视觉功能的丧失有关，从而导致更好地理解 疾病病理生理学。该知识将通知以下项目的端点和注册标准的选择 即将进行的STGD1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.