Natural History of ABCA4-Related Retinopathies

1. ABCA4视网膜病变自然史研究

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.