Treating early stage diabetic retinopathy

治疗早期糖尿病视网膜病变

• 批准号: 10656335
• 负责人: Machelle T. Pardue
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656335
• 关键词: Affect; Aneurysm; Angiography; Animal Model; Appearance; Blindness; Blood Glucose; Blood Vessels; Carbidopa; Clinical; Clinical Management; Clinical Research; Data; Defect; Detection; Diabetes Mellitus; Diabetic Retinopathy; Disease; Dopamine; Early treatment; Electroretinography; Eye; Functional disorder; Fundus; Fundus photography; Glycosylated hemoglobin A; Hemorrhage; Individual; Knowledge; Lesion; Levodopa; Link; Measurement; Measures; Microaneurysm; Microvascular Dysfunction; Monitor; National Eye Institute; Neural Pathways; Neural Retina; Neurologist; Neuromodulator; Neuronal Dysfunction; Neurons; Optical Coherence Tomography; Outcome Measure; Participant; Pathology; Pathway interactions; Patients; Persons; Placebos; Recovery; Renal function; Retina; Retinal Diseases; Risk; Rod; Rodent Model; Sinemet; Structure; Testing; Therapeutic; United States National Institutes of Health; Veterans; Vision; Visual; Work; clinical practice; cohort; design; diabetic; diabetic patient; diagnostic biomarker; early screening; experimental study; follow-up; glycemic control; illness length; neuroprotection; ophthalmic examination; preservation; prevent; primary outcome; randomized, clinical trials; response; retinal neuron; side effect; standard of care; success; treatment duration

Diabetic Retinopathy (DR) is a leading cause of vision loss in the US. To detect DR, individuals with diabetes are instructed to receive annual eye exams until visible retinopathy such as hemorrhages or aneurysms appear that often take years to develop. Even so, treatment is only provided when visually threatening disease is detected. Our group and others have established that in people with diabetes, retinal neuronal dysfunction precedes clinically visible retinopathy. Non-invasive recordings of retinal function using the electroretinogram (ERG) have shown dysfunction with diabetes, particularly in the oscillatory potentials (OPs) that are generated by inner retinal neurons. A fundamental gap in our knowledge of DR pathology is whether neuronal dysfunction is associated with or causal to the late stage vascular defects. Our overall hypothesis is that neuronal defects precede vascular defects in DR and that treating neuronal deficits early in DR will prevent late stage vascular defects that result in vision loss. Dopamine, a key neuromodulator in the retina, is reduced in DR. We demonstrated that treating rodent models of diabetes with levodopa, a dopamine precursor, is neuroprotective for neuronal dysfunction. Importantly, we also showed that in patients with diabetes and retinal dysfunction, but without retinopathy, levodopa taken for only 2 weeks restored retinal dysfunction to normal levels. Thus, our preliminary data suggest that earlier screening and treatment are possible to prevent or delay retinal dysfunction in early DR. Since current clinical management of DR is directed at more advanced stages of disease when vascular defects are present, it is critical to determine if levodopa will also prevent vascular pathology. We propose the following specific aims to investigate the link between neuronal and vascular defects in DR by using neuronal (dim flash ERG) and vascular (fundus photography and optical coherence tomography angiography) primary outcome measures: Aim 1: Investigate whether the appearance of early neuronal dysfunction predicts late stage vascular pathology in diabetes. We propose follow-up testing on a cohort of participants with diabetes, and normal or delayed OPs, from a prior clinical study to determine how many develop signs of retinal vascular defects after 3-5 years. Aim 2: Determine whether levodopa treatment initiated at detection of retinal dysfunction will prevent retinal dysfunction and vascular defects. We will conduct a randomized clinical trial with levodopa versus placebo using participants with diabetes and confirmed OP delays from two groups: 1) without retinopathy and 2) with the earliest signs of DR (microaneurysms). Patients will receive levodopa or placebo twice daily for 6- or 24-months. For the 6-month duration, testing will be done at baseline, 3 months and 6 months. Patients will then return to routine standard of care and be re-tested at 12 and 24 months. For the 24- month duration, testing will be done at baseline and every 3 months until 24 months. Participants will be carefully monitored for levodopa side effects with the assistance of a neurologist. Determining the association between neuronal and vascular defects in DR is critical to shifting clinical practice toward early diagnostic markers, a move that could transform the way DR is monitored and treated, ultimately leading to better preservation of normal visual function.

糖尿病视网膜病变(DR)是美国视力丧失的主要原因。要检测DR，患有 糖尿病患者被指示接受年度眼科检查，直到可见视网膜病变，如出血或 动脉瘤的出现往往需要数年时间才能形成。即便如此，只有在视觉上才能提供治疗。 检测到有威胁的疾病。我们的团队和其他人已经证实，在糖尿病患者中，视网膜 神经元功能障碍是临床可见视网膜病变的先兆。视网膜功能的无创记录使用 视网膜电信号(ERG)显示糖尿病患者存在功能障碍，尤其是振荡电位。 (OPs)是由视网膜内神经元产生的。我们对DR病理学知识的一个根本差距是 神经元功能障碍是否与晚期血管缺陷相关或导致。我们的整体 假说是，在糖尿病视网膜病变中，神经元缺陷先于血管缺陷，治疗神经元缺陷 早期DR将防止导致视力丧失的晚期血管缺陷。 多巴胺，视网膜中的一个关键的神经调节剂，在Dr. 左旋多巴(一种多巴胺前体)的糖尿病模型对神经元功能障碍具有神经保护作用。 重要的是，我们还表明，在有糖尿病和视网膜功能障碍但没有视网膜病变的患者中， 服用左旋多巴2周后，视网膜功能障碍恢复到正常水平。因此，我们的初步数据 提示早期筛查和治疗有可能预防或延缓早期DR患者的视网膜功能障碍。 由于目前对DR的临床治疗是针对更晚期的疾病，当血管 存在缺陷，关键是要确定左旋多巴是否也能预防血管病变。 我们提出了以下具体目标来研究神经元和血管缺陷之间的联系。 使用神经元(暗闪光ERG)和血管(眼底照相和光学相干断层扫描)进行DR 血管造影术)主要结果指标： 目的1：研究早期神经元功能障碍的出现是否预示晚期 糖尿病的血管病理学。我们建议对一组糖尿病患者进行跟踪测试，并 正常或延迟的OPS，来自先前的临床研究，以确定有多少人发展为视网膜血管迹象 3-5年后出现缺陷。 目的2：确定在检测到视网膜功能障碍时开始左旋多巴治疗是否会 预防视网膜功能障碍和血管缺陷。我们将对左旋多巴进行随机临床试验。 与安慰剂相比，使用来自两组的糖尿病患者和确诊的OP延迟的参与者：1)没有 视网膜病变和2)最早的DR征象(微动脉瘤)。患者将接受左旋多巴或安慰剂 每天两次，持续6个月或24个月。对于6个月的持续时间，测试将在基线、3个月和6个月进行 月份。然后，患者将恢复到常规护理标准，并在12个月和24个月时进行重新测试。对于24名- 持续一个月，测试将在基线上进行，并每3个月进行一次，直到24个月。参与者将是 在神经科医生的协助下，仔细监测左旋多巴的副作用。 确定糖尿病视网膜病变中神经元和血管缺陷之间的关联对临床转移至关重要。 实践早期诊断标志物，这一举措可能会改变监测和治疗DR的方式， 最终导致更好地保存正常的视觉功能。