Structure-Function Relationships in Stargardt Disease.

Stargardt 病的结构-功能关系。

基本信息

批准号：
10288617
负责人：
Xiangrong Kong
金额：
$ 24.56万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10288617
关键词：
Address Adolescent Adult Affect Age related macular degeneration Area Atrophic Blindness Child Clinical Communities Data Data Collection Diabetic Retinopathy Disease Disease Progression Early treatment Enrollment Equation Europe Evaluation Eye Functional disorder Fundus Future Genes Glaucoma Goals Gold Human Resources Image Impairment Inherited International Knowledge Legal Blindness Lesion Linear Models Measures Molecular Mutation Natural History Optical Coherence Tomography Optics Outcome Outcome Measure Participant Patients Pharmacologic Substance Pharmacology Phase Phenotype Play Prospective Studies Protocols documentation Reading Retina Rod Role Secondary to Site Specific qualifier value Standardization Stargardt&apos s disease Stem cell transplant Structure Structure-Activity Relationship Surrogate Endpoint Testing Therapeutic Thick Vision Visit Visual Acuity autosomal recessive trait base clinically significant design disease natural history early phase clinical trial efficacy trial experience follow-up functional outcomes gene replacement interest international center longitudinal analysis loss of function macula macular dystrophy novel therapeutics participant enrollment participant retention success tomography treatment trial

项目摘要

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.

项目概要/摘要 ABCA4 基因相关的 Stargardt 病 (STGD1) 是最常见的青少年黄斑病营养不良，可影响儿童和成人。它作为常染色体隐性遗传。与 ABCA4 基因突变有关的患者会经历缓慢进行性的视力丧失。功能，尤其是中心视力，几十年内可达到法定失明。 STGD1 的批准治疗方法包括药物治疗、基因替代治疗。未来 STGD1 治疗试验的成功将取决于干细胞移植方法。监管机构更喜欢适当选择的试验终点。然而，由于 STGD1 试验中视觉功能丧失的速度较慢，因此可能效率低下。通过眼底自发荧光（FAF）测量的视网膜结构参数（SP）。和光学相干断层扫描（OCT）成像在临床上广泛用于追踪疾病然而，在接受 SP 进展作为试验终点之前，监管机构需要证据 SP 和功能结果之间的重要关系，包括横截面结构变化与“未来临床”之间的关系和纵向关联 STGD1 尚未充分证明此类证据（或缺乏）。 Stargardt 病继发性萎缩进展 (ProgStar) 前瞻性研究，包括其 Stargardt 病中视杆细胞功能的辅助暗视微视野评估 (SMART) 研究是一项针对 259 名经分子证实的 STGD1 患者进行的多中心国际研究，旨在产生自然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关联具有最佳矫正视力 (BCVA) 和明视黄斑敏感性的功能结果其次，评估横断面和纵向关联。 OCT 得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。将展示 FAF 和 OCT 衍生的 SP、数量级以及表型条件，与视觉功能丧失相关，从而导致更好地理解这些知识将为终点选择和入组标准提供信息。即将进行的 STGD1 治疗试验。