Natural History of ABCA4-Related Retinopathies

设计：在这项自然史研究中，参与者将被随访五年。参与者将通过其他现有的NIH方案招募，例如NEI评估和治疗试验（08-EI-0169），NEI筛选方案（08-EI-0102）和国家眼科疾病基因分型和表型网络，II期方案（eyeGENE II，10-EI-N164），或通过审查相关医疗记录和基因检测后从外部临床医生转诊。所有参与者将接受标准化的病史/眼科史和完整的基线眼部检查，包括无创电生理学检查（例如，视网膜电描记术），心理生理学（例如，微视野检查，静态视野检查），和诊断成像检查（例如，光学相干层析成像）。 参与者将在第一年接受三次检查（即，基线检查、第6个月和第12个月）。第一年后，他们将在接下来的四年里每年返回NEI诊所。本研究将需要至少7次研究访视。根据临床和研究情况，研究者可以决定以更频繁的时间间隔观察受试者。作为DNA和血清库研究的一部分，参与者将被要求提交血液样本，他们将可以选择提供3 mm的皮肤穿刺活检，以促进细胞水平的研究。 结局指标：这项研究的主要结果是建立一个ABCA 4相关视网膜病变参与者队列，次要结果是建立一个ABCA 4相关视网膜病变参与者累积队列的血浆、DNA和皮肤成纤维细胞样本库。本研究的探索性结果包括：1）制定未来研究的临床结局指标，2）获取和初步分析数据，这些数据可能会促进我们对ABCA 4相关视网膜病变中基因型-表型相关性的理解。潜在的探索性结果包括：1）从皮肤成纤维细胞样品产生iPS细胞，2）将产生的iPS细胞分化成RPE和/或神经视网膜细胞，和3）使用参与者特异性RPE和/或神经视网膜细胞进行HTP药物筛选以鉴定新的潜在治疗化合物。在该方案中获得的细胞可以是遗传修饰的，并且可以用于体内研究。 自上次报告以来，我们扩大了本方案的入组人数，并启动了对可用患者两年数据的分析。 我们特别关注功能性测量，如通过MP 1测量的视网膜敏感度和光学相干断层扫描的结构变化。 此外，我们正在使用自体荧光图像分析随时间的变化，并致力于研究新的分析技术。

Design: In this natural history study, participants will be followed for five years. Participants will be recruited through other pre-existing NIH protocols, such as the NEI Evaluation and Treatment Trial (08-EI-0169), the NEI Screening Protocol (08-EI-0102), and the National Ophthalmic Disease Genotyping and Phenotyping Network, Phase II protocol (eyeGENE II, 10-EI-N164), or through referral from an outside clinician after a review of pertinent medical records and genetic testing. All participants will undergo a standardized medical/ophthalmic history and a complete baseline eye examination, including non-invasive electrophysiology (e.g., electroretinography), psychophysiology (e.g., microperimetry, static perimetry), and diagnostic imaging examinations (e.g., optical coherence tomography). The participants will be examined three times over the course of the first year (i.e., baseline examination, Month 6, and Month 12). After the first year, they will return to the NEI clinic on an annual basis for the next four years. This study will require a minimum of seven study visits. Participants may be seen at more frequent intervals at the investigators discretion, depending on the clinical and research situation. Participants will be required to submit a blood sample as part of the study for DNA and serum banking, and they will have the option to provide a 3 mm punch skin biopsy to facilitate research at a cellular level. Outcome Measures: The primary outcome for this study is the establishment of a cohort of participants with ABCA4-related retinopathies, and the secondary outcome is the creation of a repository of plasma, DNA, and skin fibroblast samples from the accrued cohort of ABCA4-related retinopathy participants. Exploratory outcomes for this study include: 1) the formulation of clinical outcome measures for future studies and 2) the acquisition and preliminary analysis of data that may advance our understanding of genotype-phenotype correlations in ABCA4-related retinopathies. Potential exploratory outcomes include: 1) the generation of iPS cells from the skin fibroblast samples, 2) the differentiation of the generated iPS cells into RPE and/or neural retinal cells, and 3) the use of the participant-specific RPE and/or neural retinal cells to perform HTP drug screens to identify novel potential therapeutic compounds. The cells obtained in this protocol may be genetically modified and may be used for in vivo research. Since the time of the last report, we have expanded enrollment for this protocol and have initiated analysis of the two-year data on patients where this is available. We are specifically addressing functional measures such as retinal sensitivity as measured by MP1 and structural changes on optical coherence tomography. Additionally, we are analyzing change over time using autofluorescent images and working on novel analysis techniques looking at flecks.