Highly sensitive measurements of disease progression in rare disorders: Developing and validating a multimodal model of retinal degeneration in Stargardt disease.
Highly sensitive measurements of disease progression in rare disorders: Developing and validating a multimodal model of retinal degeneration in Stargardt disease.
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DOI：
10.1371/journal.pone.0174020
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Hoyng CB
中科院分区：
文献类型：
--
作者：
Lambertus S;Bax NM;Fakin A;Groenewoud JM;Klevering BJ;Moore AT;Michaelides M;Webster AR;van der Wilt GJ;Hoyng CB
每种遗传性视网膜疾病都很罕见，但它们共同影响着全世界数百万人。目前还没有治疗这些致盲性疾病的方法，但有希望的新选择-包括基因治疗-正在出现。可以说，最普遍的视网膜营养不良是Stargardt病。在每种情况下，ABCA 4变体（迄今已鉴定> 900种）和修饰因子的特定组合实际上是独特的。它解释了巨大的表型异质性，包括功能和结构进展的可变速率，从而潜在地限制了I/II期临床试验在少数患者中评估新型疗法疗效的能力。为了解决这个问题，我们开发并验证了一种基于视网膜变性结构测量的疾病进展敏感可靠的复合临床试验终点。我们使用了来自荷兰（开发队列，n = 14）和英国（外部验证队列，n = 18）的早发性Stargardt患者的纵向数据。复合终点来自最佳矫正视力、眼底自发荧光和谱域光学相干断层扫描。加权优化技术从复合终点中排除了视力。优化后，终点优于每个单变量结果，并显示每年平均进展0.41°视网膜偏心（95%置信区间，0.30-0.52）。与实际纵向值相比，模型准确预测进展（R2，0.904）。这些特性在验证队列中基本保持不变（0.43°/年[0.33-0.53];预测：R2，0.872）。随后，我们进行了一项为期两年的试验模拟，其中仅使用了14名患者，检测到疾病进展减少了25%，统计功效为80%。这些结果表明，反映结构性黄斑变化的多模态终点为Stargardt病的疾病进展提供了敏感的测量方法。它可以在罕见疾病的新的治疗方式的评价非常有用。
Each inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options—including gene therapy—are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients. To accommodate this problem, we developed and validated a sensitive and reliable composite clinical trial endpoint for disease progression based on structural measurements of retinal degeneration. We used longitudinal data from early-onset Stargardt patients from the Netherlands (development cohort, n = 14) and the United Kingdom (external validation cohort, n = 18). The composite endpoint was derived from best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography. Weighting optimization techniques excluded visual acuity from the composite endpoint. After optimization, the endpoint outperformed each univariable outcome, and showed an average progression of 0.41° retinal eccentricity per year (95% confidence interval, 0.30–0.52). Comparing with actual longitudinal values, the model accurately predicted progression (R2, 0.904). These properties were largely preserved in the validation cohort (0.43°/year [0.33–0.53]; prediction: R2, 0.872). We subsequently ran a two-year trial simulation with the composite endpoint, which detected a 25% decrease in disease progression with 80% statistical power using only 14 patients. These results suggest that a multimodal endpoint, reflecting structural macular changes, provides a sensitive measurement of disease progression in Stargardt disease. It can be very useful in the evaluation of novel therapeutic modalities in rare disorders.