Gyrate Atrophy Ocular and Systemic Study (GYROS)

回旋萎缩眼部和全身研究 (GYROS)

• 批准号: 10573885
• 负责人: Allison Renee Ayala
• 金额: $ 40万
• 依托单位: JAEB CENTER FOR HEALTH RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573885
• 关键词: Gyrate; Atrophy; Ocular; Systemic; Study

1 Project Summary/Abstract for GYROS 2 Gyrate atrophy is a rare inherited chorioretinal degeneration that is associated with 3 hyperornithinemia caused by autosomal recessive mutations in the ornithine aminotransferase 4 (OAT) gene and leads to severe loss of vision. The current standard of care treatment is a 5 highly burdensome arginine-restricted diet (ARD) fraught with management complications. The 6 principal investigators are currently developing a gene augmentation therapy, a potential 7 treatment strategy that may preserve or improve vision while avoiding or reducing the 8 need for ARD. To facilitate a future interventional clinical trial, there is a need to characterize 9 the natural history of OAT-related ocular and systemic disease progression. The study aims are: 10 1. Natural History – Characterize the natural history of ornithine levels and retinal 11 degeneration (RD) associated with disease-causing OAT variants in the presence of 12 standard dietary treatment regimens over 4 years, using metabolic measures of fasting 13 plasma and blood spot amino acids panels, functional and structural measures of RD, 14 and patient-reported outcome measures. 15 2. Metabolic-Structure-Function Relationships – Explore the relationships between 16 structural and functional RD outcome measures and plasma ornithine levels. 17 3. Identify Rapid Progressors – Explore the relationship of possible risk factors 18 (genotype, phenotype, environmental, standard care dietary regimen) with severity and 19 progression of outcome measures. 20 This natural history study will inform the future interventional clinical trial design as follows: 21  Determine within-patient variability of ornithine levels 22  Develop quantitative measures of progression of the area of preserved retina and 23 establish its reproducibility, sensitivity to change, and relationship with other measures 24  Establish rates of progression of functional RD, structural RD, and patient-reported 25 outcome measures, and determine which measures are most sensitive to change 26  Determine primary time points and duration for a planned future treatment trial 27  Use variability and inter-eye correlation of outcomes for trial sample size calculations 28  Identify candidates for the future trial, including eligibility criteria based on risk factors 29 and cut points for severity of disease most likely to benefit from treatment 30  Establish study procedures and workflows

1 GYROS的项目摘要/摘要 2回旋状萎缩是一种罕见的遗传性脉络膜视网膜变性， 3例由鸟氨酸转氨酶常染色体隐性突变引起的高鸟氨酸血症 4（OAT）基因，导致严重的视力丧失。目前的标准治疗是 5高度负担的限制摄入尼古丁的饮食（ARD），充满了管理并发症。的 6名主要研究人员目前正在开发一种基因增强疗法， 7种治疗策略，可以保留或改善视力，同时避免或减少 八是要有德。为了促进未来的干预性临床试验，需要描述 9 OAT相关眼部和全身疾病进展的自然史。研究的目的是： 10 1.自然史-表征鸟氨酸水平和视网膜病变的自然史 11与致病OAT变体相关的变性（RD）， 12个标准的饮食治疗方案超过4年，使用禁食代谢措施 13个血浆和血斑氨基酸组，RD的功能和结构测量， 14和患者报告的结局指标。 十五两代谢-结构-功能关系-探索 16个结构和功能RD结局指标和血浆鸟氨酸水平。 17 3.确定快速进展者-探索可能的风险因素之间的关系 18例（基因型、表型、环境、标准护理饮食方案）严重程度和 19个结果测量的进展。 20这项自然史研究将为未来的干预性临床试验设计提供如下信息： 21.确定患者内鸟氨酸水平的变异性 22.开发保存视网膜区域进展的定量测量， 23建立其可重复性、对变化的敏感性以及与其他措施的关系 24.确定功能性RD、结构性RD和患者报告的 25个结果指标，并确定哪些指标对变化最敏感 26.确定计划的未来治疗试验的主要时间点和持续时间 使用结果的变异性和眼间相关性计算试验样本量 28.确定未来试验的候选人，包括基于风险因素的资格标准 29和最有可能从治疗中获益的疾病严重程度的临界点 30.建立研究程序和工作流程