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.

项目概要 溶酶体贮积病是病理性积累引起的全身代谢紊乱 各种细胞和器官中的副产物，包括法布里病是最常见的。 溶酶体贮积病，由 X 连锁 GLA 基因突变导致缺陷所致 α-半乳糖苷酶 A (α-Gal A) 逐渐积累，从而产生 肾功能衰竭、心功能不全、脑血管疾病导致生活质量缩短和降低， 胃肠道症状和慢性疼痛患者还患有特有的轮状角膜。 诊断时通常会出现其他症状，包括白内障、结膜和视网膜症状。 重要的是，弯曲度和动脉瘤扩张之间存在直接相关性。 伴有轮叶的法布里病的某些眼部表现和疾病严重程度通常会导致 眼部相关发现与其他器官系统疾病的初步诊断时机尚不明确。 由于小鼠患者群体的异质性，很难在人类中进行研究。 模型已用于酶替代疗法（ERT）的开发，但受到以下限制： 事实上，它们不能重现使用 Dark Agouti α-Gal A 基因敲除动物的眼睛表型。 我们建立了患者角膜、晶状体和视网膜血管变化模型，旨在评估 基因敲除大鼠和人类的眼部疼痛和视网膜表型以前未在实验中评估过 在治疗这种罕见疾病的队列中，我们独特的方法整合了多种药物的互补优势。 动物模型，提供了研究大量受控人群的机会，而人类研究 我们建议通过以下具体目标来确定病理学的临床意义： 1) 评估法布里病 α-Gal A KO 大鼠模型眼部病理的程度和时间进程 以及早期与晚期 ERT 的效果，以及 2) 评估患有法布里病的人类受试者的眼部情况 在 α-Gal A KO 中观察到的临床显着疾病之前出现的疼痛和亚临床眼部变化 这项工作预计将对我们了解溶酶体储存产生重大影响。 通过使用重现眼部症状的动物模型来阐明疾病的时间进程 法布里病的眼部病理学与全身症状相关。这些发现将有助于 确定 ERT 启动的最佳时机和新疗法的功效，同时提供 对其他溶酶体或代谢疾病的眼部病理学的机制洞察。