Structure-Function Relationships in Stargardt Disease.

Stargardt 病的结构-功能关系。

• 批准号: 10489833
• 负责人: Xiangrong Kong
• 金额: $ 19.85万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10489833
• 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' 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; 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' 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

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.

项目摘要/摘要 ABCA4基因相关的Stargardt疾病（STGD1）是最常见的少年黄斑 营养不良，会影响儿童和成人。它被继承为常染色体不必要的特征 与ABCA4基因中的突变有关。患者的视觉渐进式丧失缓慢 功能，尤其是中央视觉，并且可以在几十年内达到法律失明。目前没有 批准的STGD1治疗。潜在的治疗选择包括药学，基因置换 和干细胞移植方法。未来的STGD1治疗试验的成功将取决于 适当选择的试验终点。监管机构更喜欢视觉功能结果 但是，由于STGD1试验的无效 疾病自然史。通过眼底自动荧光（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 进展。但是，在接受SP作为试验端点之前，监管机构需要证据 SP与功能结果之间的显着关系，包括两个横截面 关系以及结构变化与未来诊所之间的纵向关联 大量结果”。STGD1尚未很好地证明此类证据（或缺乏）。 继Stargardt疾病（Progstar）前瞻性研究的萎缩进展，包括其 辅助Scotic scotopic微磁线对Stargardt疾病（SMART）研究中的Rod功能的评估为 一项对259个分子确认的STGD1患者的多中心国际研究，生成天然 历史数据超过2年的随访。利用这些研究的数据，我们的目标是：首先 评估FAF衍生参数在萎缩病变大小上的横截面和纵向关联 具有最佳校正视力（BCVA）的功能结果，并具有照光的黄斑敏感性 和SCOTOPIC微量学测试。第二，评估横截面和纵向关联 OCT在视网膜完整性上衍生的参数，包括内部和内部和完整区域 外部视网膜层，具有BCVA的功能结果，以及光波和Scotopic Macula敏感性。 将使用具有广义估计方程的广义线性模型。知识学到了 将证明FAF和OCT衍生的SP，在什么磁化率以及表型下 条件与视觉功能的丧失有关，从而更好地理解 疾病病理生理学。知识将为终点的选择和入学标准提供信息 即将进行的STGD1治疗试验。