Natural History of ABCA4-Related Retinopathies

1. ABCA 4视网膜病变自然史研究 在ABCA 4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，光学相干断层扫描，OCT）。 参加者将在第一年内接受三次考试（即，基线、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。本研究至少需要7次访视。根据临床和研究情况，研究者可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，受试者将被要求提交血液样本，他们将可以选择提供3 mm穿刺皮肤活检，以开发体外疾病模型并促进细胞生物学研究。 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诱导多能干细胞（iPSC），2）将产生的iPSC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高通量（HTP）药物筛选以鉴定新的潜在治疗性化合物。功能测量，如视网膜灵敏度测量的MP 1和OCT的结构变化正在具体解决。此外，我们正在使用自体荧光图像分析随时间的变化，并研究新的分析技术，研究flectin的进展/自然史。 一些登记的参与者已经完成了原计划的五年自然史，他们的随访期已经延长。将对这些患者进行一组选定的高数据产量试验。此外，OCT参数已被确定为在未来的临床试验中用作结局指标。 我们使用深度学习方法分析了这项自然史研究中132只眼睛（66名患者）的OCT扫描，并将我们的发现与基因型相关联。 我们发现的进展率为0.09mm/y（EZ带损失面积的平方根变换），并表明外核层减薄延伸到EZ损失面积之外。 我们已经将这些患者的基因型信息关联起来。 2.二甲双胍给药减缓ABCA 4视网膜病变的进展 根据上述人群研究的现有数据，一项开放标签II期临床试验已获得FDA和NIH IRB批准，并于2020年11月开始（20-EI-0163）。该试验的目的是测试FDA批准的化合物二甲双胍在减缓疾病进展速度方面的疗效。 根据自然史研究方案筛选的受试者将具有病史和家族史。他们将完成一份关于他们的视力和日常活动的问卷。他们将接受身体检查和广泛的眼科检查和视力测试。可以抽取血液样本。受试者将口服二甲双胍24个月，并将每6个月进行一次研究访视进行监测。研究随访将继续额外12个月。受试者将在进入研究时接受每日500 mg二甲双胍速释制剂。该剂量将以500 mg增量每周递增一次，直至达到每日最大剂量2000 mg。此后，他们将改用缓释制剂（1000毫克，每天两次，口服）。如果不能耐受2000 mg/天，剂量可降至最低1000 mg/天。由于二甲双胍缓释未被FDA批准用于17岁以下儿童，因此17岁以下的受试者将继续使用速释制剂。 由于新型冠状病毒肺炎（COVID-19，即2019冠状病毒病）大流行，诊所的工作在过去一年里比平时慢，但最近几周已开始恢复正常。

1. ABCA4 Retinopathy Natural History Study In the ABCA4 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, OCT). Participants will be examined three times over the course of the first year (i.e., baseline, 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 visits. Participants may be seen at more frequent intervals at the investigator's 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 develop in vitro disease models and facilitate cell biology investigations. 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 induced pluripotent stem cells (iPSCs) from the skin fibroblast samples, 2) the differentiation of the generated iPSC into RPE and/or neural retinal cells, and 3) the use of the participant-specific RPE and/or neural retinal cells to perform high throughput (HTP) drug screens to identify novel potentially therapeutic compounds. Functional measures such as retinal sensitivity as measured by MP1 and structural changes on OCT are being specifically addressed. Additionally, we are analyzing change over time using autofluorescence images and working on novel analysis techniques looking at the progression/natural history of flecks. A number of enrolled participants have completed the originally planned five-year natural history and their period of follow-up has been extended. A selected battery of assays with high data yield will be performed on these patients. Furthermore, OCT parameters have been established to be used as outcome measure in future clinical trials. We have used a deep learning approach to analyze the OCT scans of 132 eyes (66 patients) from this natural history study and correlate our findings with genotype. We found a progression rate of 0.09mm/y (square root transform of are of EZ band loss) and show that outer nuclear layer thinning extends beyond the aera of EZ loss. We have correlated this genotypic information from these patients. 2. Metformin administration to slow down progression of ABCA4 Retinopathy Based on currently available data from the above population study, an open label phase II clinical trial has received FDA and NIH IRB approval to proceed and was started in November 2020 (20-EI-0163.) The goal of the trial is to test the efficacy of the FDA-approved compound metformin in slowing the rate of disease progression. Participants screened under the natural history study protocol will have a medical and family history. They will complete a questionnaire about their vision and daily activities. They will undergo a physical exam and extensive eye exam and vision testing. A blood sample may be drawn. Participants will take metformin by mouth for 24 months and will be monitored with study visits every 6 months. Study follow-up will continue for an additional 12 months. Participants will receive an immediate release formulation of metformin of 500mg daily at study entry. This dose will be titrated up weekly in 500mg increments to reach 2000mg daily maximum. Thereafter, they will switch to an extended-release formulation (1000mg twice a day by mouth). If 2000mg/day is not tolerated, the dose could be reduced to a minimum of 1000mg/day. Since metformin extended release is not FDA-approved for children under the age of 17, participants under 17 will remain on the immediate release formulation. Because of the Covid-19 pandemic, work in the clinic has been slower than usual for the past year but has started to return to normal in recent weeks.