Natural History of ABCA4-Related Retinopathies

1.ABCA4视网膜病变自然史研究 在ABCA4自然历史研究中，参与者将被跟踪五年。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筛查方案(08-EI-0102)和国家眼病基因分型和表型网络第二阶段方案(EYGENE II，10-EI-N164)，或者在审查相关医疗记录和基因测试后通过外部临床医生转介。所有参与者将接受标准化的医疗/眼科病史和完整的基线眼科检查，包括非侵入性电生理学(例如视网膜电生理检查)、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))。 参与者将在第一年的过程中接受三次检查(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回到NEI诊所。这项研究将需要至少七次访问。根据临床和研究情况，研究人员可能会更频繁地观察参与者。参与者将被要求提交血液样本，作为DNA和血清库研究的一部分，他们将可以选择提供3毫米冲压皮肤活检，以建立体外疾病模型，并促进细胞生物学研究。 这项研究的主要结果是建立了ABCA4相关视网膜病变的参与者队列，次要结果是从ABCA4相关视网膜病变参与者的累积队列中创建了血浆、DNA和皮肤成纤维细胞样本库。这项研究的探索性成果包括：1)为未来的研究制定临床结果衡量标准；2)获取和初步分析数据，以促进我们对ABCA4相关视网膜病变的基因-表型相关性的理解。潜在的探索性成果包括：1)从皮肤成纤维细胞样本中产生诱导多能干细胞(IPSC)，2)将产生的IPSC分化为RPE和/或神经视网膜细胞，以及3)使用参与者特有的RPE和/或神经视网膜细胞进行高通量(HTP)药物筛选，以确定新的潜在治疗化合物。功能测量，如MP1测量的视网膜敏感度和OCT的结构变化正在被特别处理。此外，我们正在使用自发荧光图像分析随时间的变化，并致力于研究新的分析技术，以观察斑点的进展/自然历史。 一些登记的参与者已经完成了原计划的五年自然历史，他们的随访期延长了。将对这些患者进行具有高数据产量的选定的一组分析。此外，OCT参数已被确定为未来临床试验中的结果衡量标准。 我们使用深度学习方法分析了这项自然病史研究中132只眼(66名患者)的OCT扫描，并将我们的发现与基因相关。我们得到了0.09 mm/y的速度(EZ带损失区域的平方根变换)，并表明外核层变薄扩展到了EZ带损失区域之外。我们已经将这些患者的这种基因信息联系起来。 在另一项对功能结果的单独分析中，共纳入67名参与者的134只眼，平均随访3.65年。在两年的时间间隔中，基于微视野的周边敏感度(2of 0.73，0.53，0.83；-1.79分贝/年-2.2，-1.37)和平均敏感度(2 0.62，0.38，0.76；-1.28分贝/年，-1.67，-0.89)随时间变化最大，但只有71.6%的受试者能记录到。在五年的时间间隔中，暗适应的ERGa波和b波的幅度也显示出明显的随时间的变化(例如，DA 30a波的幅度具有2 0.540.34，0.68；-0.02log10(V)/yr-0.02，-0.01)。在基于ERG的发病年龄中，该基因可以解释很大一部分变异。R2/0.73) 2.应用二甲双胍延缓ABCA4视网膜病变的进展 根据上述人群研究的现有数据，开放标签II期临床试验已获得FDA和NIH IRB的批准，并于2020年11月启动(20-EI-0163)。这项试验的目的是测试FDA批准的复合二甲双胍在减缓疾病进展速度方面的有效性。 根据自然历史研究方案进行筛选的参与者将有病史和家族史。他们将完成一份关于他们的视力和日常活动的问卷。他们将接受体检、广泛的视力检查和视力测试。可以抽取血样。参与者将口服二甲双胍24个月，并每6个月进行一次研究访问进行监测。研究随访将再持续12个月。参与者将在研究开始时立即获得每日500毫克的二甲双胍释放剂。这个剂量将以500毫克为增量每周滴定，以达到每天2000毫克的最大剂量。此后，他们将改用缓释制剂(每天两次，每次1000毫克)。如果不能耐受2000毫克/天，剂量可以减少到最低1000毫克/天。由于FDA没有批准17岁以下的儿童使用二甲双胍缓释剂，17岁以下的参与者将继续服用即刻释放制剂。 到目前为止，我们已经招募了24名参与者，其中大多数人已经耐受了药物，并能够继续进行研究。两名参与者已经完成了他们的全部疗程，并处于该议定书的安全后续阶段。还有多名其他患者正在排队登记，他们已经完成了大部分/所有必需的自然病史访问。

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. In a separate analysis of functional outcomes, a total of 134 eyes from 67 participants with a mean follow-up of 3.65 years were included. In the two-year interval, the microperimetry-derived peri-lesional sensitivity (2of 0.73 0.53, 0.83; -1.79 dB/yr -2.2, -1.37) and mean sensitivity (2 of 0.62 0.38, 0.76; -1.28 dB/yr - 1.67, -0.89) showed most change over time, but could only be recorded in 71.6 % of the participants. In the five-year interval, the dark-adapted ERG a- and b-wave amplitude showed marked change-over-time as well (e.g., DA 30 a-wave amplitude with an 2 of 0.54 0.34, 0.68; -0.02 Log10(V)/yr -0.02, -0.01). The genotype explained a large fraction of variability in the ERG-based age-of-disease-initiation (adj. R2 of 0.73) 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. To date, we have enrolled 24 participants, most of whom have tolerated drug and were able to continue on the study. Two participants have completed their full course of treatment and are on the safety follow-up stage of the protocol. There are multiple other patients are in line to enroll, having completed most/all of the required natural history visits.