Gene regulation, genetic mechanisms and development of potential therapies for corneal endothelial dystrophies

角膜内皮营养不良的基因调控、遗传机制和潜在疗法的开发

• 批准号: MR/Y019911/1
• 负责人: Alice Davidson
• 金额: $ 75.75万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY019911%2F1
• 关键词: Gene; regulation; genetic; mechanisms; development

Background: The cornea is the transparent window situated at the front of the eye. It protects the eye from the external environment and focuses light onto the retina. The inner most part of the cornea is a specialised layer of corneal endothelial cells. These cells perform a pump-like mechanism removing water from the outer layers of the cornea, to ensure that the tissue is optimally hydrated, while also regulating the movement of crucial nutrients into the rest of the cornea. Corneal endothelial dystrophies (CEDs) are a group of genetic diseases that result in dysfunction of this specialised cellular layer. They results in corneal swelling, clouding and consequently visual impairment, and in some instances, blindness. Fuchs Endothelial Corneal Dystrophy (FECD) is an age-related disease and the most common CED by far, affecting 4.5% of people >50 years of age. Up to 80% of cases have the same genetic cause, termed a mutation, that affects a repetitive part of the human genome. Other much rarer types of CEDs include a disorder called Posterior Polymorphous Corneal Dystrophy. In recent years, we and others have identified multiple mutations in numerous genes that cause rarer CEDs. However, we still do not know the cause of approximately 25% of total CED cases, and for the cases in which we know the mutations responsible, we still do not fully understand how these mutations cause disease. Clinical Need: Corneal transplantation is currently the only treatment option available for CED patients experiencing visual loss, but the long-term survival of grafts is poor, and there is a global shortage of donor tissues. Coupled with the age-related nature of FECD, this means that in our globally aging society there is an urgent clinical need for alternative and ideally preventative, or disease-delaying, therapies to be developed. Aim: This research program aims to 1) discover genetic causes and risk factors that predispose individuals to developing CEDs, 2) define how these genetic risk factors and/or causes lead to impaired corneal function, and 3) use this knowledge to develop innovative new therapies. Methods: DNA samples from CED patients will be analysed using a range of genetic methods to identify genetic causes and modifiers of disease. In parallel, using donated tissues removed during corneal transplant surgery, we will establish and implement a range of specialist methods to grow the cornea cells and tissue in a dish to investigate how particular mutations cause cell dysfunction and disease. This knowledge, in combination with the optimised cellular disease models, will be harnessed to pioneer the pre-clinical development of gene-directed treatment strategies in a safe and disease-relevant context. Expected outcomes of the study: This study will identify genetic causes and modifiers of CEDs that will, in the short-term, facilitate earlier pre-symptomatic detection of disease in affected families, inform genetic counselling and may alter the clinical management of disease. In the longer-term insight gained will enable clinicians to better recognise individuals at risk of developing CEDs eligible for preventatives therapies. In parallel, knowledge gained from studying molecular disease mechanisms will accelerate the design and development of gene targeted CED therapies for these sight threatening conditions. Mechanistic discoveries are also anticipated to offer novel insights into biomarkers and risk prediction strategies for other categories of human disease that are similarly attributed to mutations that affects a repetitive part of the human genome, such as Huntington's disease and myotonic dystrophy. In summary, this research program has the potential to transform CED patient care and generate broad reaching impact across the areas of ocular biology, personalised medicine, human genetics and functional genomics.

背景：角膜是位于眼睛前部的透明窗口。它保护眼睛免受外部环境的影响，并将光线聚焦到视网膜上。角膜的最里面部分是角膜内皮细胞的特化层。这些细胞执行类似泵的机制，从角膜外层去除水分，以确保组织得到最佳水合，同时还调节关键营养物质进入角膜其余部分的运动。角膜内皮营养不良（CED）是一组遗传性疾病，导致这一专门的细胞层功能障碍。它们会导致角膜肿胀、浑浊，从而导致视力障碍，在某些情况下甚至失明。Fuchs内皮角膜营养不良（FECD）是一种年龄相关性疾病，是迄今为止最常见的CED，影响4.5%的50岁以上人群。高达80%的病例具有相同的遗传原因，称为突变，影响人类基因组的重复部分。其他更罕见的CED类型包括一种称为后多形角膜营养不良的疾病。近年来，我们和其他人已经在许多基因中发现了导致罕见CED的多个突变。然而，我们仍然不知道大约25%的CED病例的原因，对于我们知道突变的病例，我们仍然不完全了解这些突变是如何导致疾病的。临床需求：角膜移植是目前唯一可用于经历视力丧失的CED患者的治疗选择，但移植物的长期存活率很差，并且全球缺乏供体组织。再加上FECD与年龄相关的性质，这意味着在我们的全球老龄化社会中，迫切需要开发替代性和理想的预防性或延迟疾病的治疗方法。目的：该研究项目旨在1）发现使个体易患CED的遗传原因和风险因素，2）确定这些遗传风险因素和/或原因如何导致角膜功能受损，3）利用这些知识开发创新的新疗法。方法：将使用一系列遗传学方法分析CED患者的DNA样本，以确定疾病的遗传原因和修饰剂。同时，使用角膜移植手术中取出的捐赠组织，我们将建立和实施一系列专业方法，在培养皿中培养角膜细胞和组织，以研究特定突变如何导致细胞功能障碍和疾病。这些知识与优化的细胞疾病模型相结合，将用于在安全和疾病相关的背景下开创基因导向治疗策略的临床前开发。本研究的预期成果：本研究将确定CED的遗传原因和修饰剂，这将在短期内促进受影响家庭中疾病的早期症状前检测，为遗传咨询提供信息，并可能改变疾病的临床管理。从长远来看，所获得的见解将使临床医生能够更好地识别有资格接受预防性治疗的CED风险的个体。同时，从研究分子疾病机制中获得的知识将加速这些视力威胁疾病的基因靶向CED疗法的设计和开发。机制的发现也有望为其他类别的人类疾病提供生物标志物和风险预测策略的新见解，这些疾病类似地归因于影响人类基因组重复部分的突变，例如亨廷顿病和强直性肌营养不良。总之，这项研究计划有可能改变CED患者护理，并在眼部生物学，个性化医学，人类遗传学和功能基因组学领域产生广泛的影响。