Diagnosis and Predictive Value of the Ocular Manifestations of Fabry Disease

法布里病眼部表现的诊断及预测价值

• 批准号: 10601130
• 负责人: Shyam Sunder Chaurasia
• 金额: $ 53.16万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601130
• 关键词: Alpha-galactosidase; Aneurysm; Angiography; Animal Model; Anterior; Blood Vessels; British; Cataract; Cells; Cerebrovascular Disorders; Cornea; Dangerousness; Darkness; Data; Development; Diagnosis; Disease; Enzymes; Esthesia; Evaluation; Event; Eye; FDA approved; Fabry Disease; Fundus photography; Gene Mutation; Genes; Glycosphingolipids; Heterogeneity; Human; Incidence; Infusion procedures; Institution; Ischemia; Journals; Kidney Failure; Knock-out; Link; Lysosomal Storage Diseases; Metabolic Diseases; Modeling; Mutation; Myocardial dysfunction; Ocular Pathology; Ophthalmology; Organ; Outcome; Pain; Pathologic; Pathology; Patients; Phenotype; Population; Predictive Value; Prevalence; Principal Investigator; Quality of life; Rare Diseases; Rattus; Recombinants; Research; Research Personnel; Retina; Retinal Vascular Occlusion; Risk; Severities; Severity of illness; Surveys; Symptoms; Systemic disease; Testing; Time; United States; Visual; Work; body system; chronic pain; clinical care; clinically significant; cohort; disabling symptom; enzyme deficiency; enzyme replacement therapy; experience; gastrointestinal symptom; human subject; imaging Segmentation; immunoreaction; insight; knockout animal; mouse model; neovascularization; novel therapeutics; ocular pain; ophthalmic examination; painful neuropathy; patient population; response

PROJECT SUMMARY Lysosomal storage diseases are systemic metabolic disorders caused by pathologic accumulation of byproducts in various cells and organs, including the eye. Fabry disease is the most common lysosomal storage disease and results from a mutation of the X-linked GLA gene causing a deficiency of the enzyme α-galactosidase A (α-Gal A). Glycosphingolipids progressively accumulate, resulting in a shorter and poorer quality of life from renal failure, cardiac dysfunction, cerebrovascular disease, gastrointestinal symptoms, and chronic pain. Patients also have pathognomonic cornea verticillata that is usually present at the time of diagnosis. Other symptoms include cataract, conjunctival and retinal tortuosity, and aneurysmal dilation. Importantly, a direct correlation exists between the prevalence of certain ocular findings and disease severity in Fabry disease with cornea verticillata often leading to the initial diagnosis. The timing of the ocular findings relative to other organ system disease is not well described and difficult to study in humans because of heterogeneity in the patient population. Mouse models have been used in the development of enzyme replacement therapy (ERT), but are limited by the fact that they do not recapitulate ocular phenotypes. Using a Dark Agouti α-Gal A knockout animal model with the corneal, lenticular, and retinal vascular changes seen in patients, we seek to evaluate both knockout rats and humans for an ocular pain and retinal phenotypes not previously evaluated in a in a cohort for this rare disease. Our unique approach integrates the complementary strengths of an animal model, giving the opportunity to study a large controlled population, while human studies determine the clinical significance of pathology. We propose to do this with the following specific aims: 1) evaluate the extent and time course of ocular pathology in a α-Gal A KO rat model of Fabry disease and the effect of early versus later ERT and 2) evaluate human subjects with Fabry Disease for ocular pain and subclinical ocular changes that precede clinically significant disease observed in α-Gal A KO rats. This work is expected to have a significant impact on our understanding lysosomal storage diseases by using an animal model that recapitulates eye symptoms to elucidate the time course of ocular pathology of Fabry disease in relation to systemic symptoms. These findings will aid in the determination of optimal timing of ERT initiation and the efficacy of new therapies, while providing mechanistic insight into the ocular pathology of other lysosomal or metabolic diseases.

项目摘要 溶酶体储存疾病是由病理积累引起的全身代谢性疾病 包括眼睛在内的各种细胞和器官中的副产物。法布里病是最常见的 溶酶体储存疾病和X连锁GLA基因的突变导致缺乏症 酶α-半乳糖苷酶A（α-GAL A）的酶。糖磷脂逐渐积累，导致 肾衰竭，心脏功能障碍，脑血管疾病的较短和较差的生活质量， 胃肠道症状和慢性疼痛。患者还患有病理性的角膜角膜菌 通常在诊断时存在。其他符号包括白内障，结膜和视网膜 曲折和动脉瘤词典。重要的是，在流行率之间存在直接相关 法布里病的某些眼部发现和疾病的严重程度和角膜角膜菌通常导致 初始诊断。眼睛发现相对于其他器官系统疾病的时机不好 由于患者群体的异质性，描述的且难以研究人类。老鼠 模型已用于开发酶替代疗法（ERT），但受到 他们不概括眼型的事实。使用深色agoutiα-gal a基因动物 具有角膜，凸耳和视网膜血管变化的模型，我们试图评估 敲除大鼠和人类的眼部疼痛和视网膜表型先前未在A中进行评估 在这种罕见疾病的队列中。我们独特的方法整合了一个的完整优势 动物模型，有机会研究大量受控人群，而人类研究 确定病理的临床意义。我们建议以以下具体目的来执行此操作： 1）评估α-gal a ko大鼠法布里疾病模型中眼病理学的程度和时间过程 以及早期与后期ERT和2）评估眼部疾病的人类受试者的影响 在α-gal a ko中观察到的临床意义疾病之前的疼痛和亚临床眼变化 老鼠。预计这项工作将对我们的理解溶酶体存储产生重大影响 通过使用概括眼症状的动物模型来阐明时间过程 Fabry疾病的眼病理学与全身症状有关。这些发现将有助于 确定ERT启动的最佳时机和新疗法的效率，同时提供 对其他溶酶体或代谢疾病的眼病理学的机械洞察力。