Models, modifiers and novel treatments of Joubert syndrome

在英国需要肾脏替代疗法（透析和移植）的4万名患者中，囊性肾病占10%。囊性肾病是一组被称为“纤毛病”的疾病的一部分，它会导致囊性肾病、视网膜变性和患者大脑异常的各种组合。目前还没有针对这些疾病的治疗方法。“纤毛病”一词涵盖了广泛的疾病，患者通常可以表现出广泛的症状。例如，同一基因的突变可能在不同的患者身上引起不同的症状。显然，这使得了解疾病原因、做出准确诊断和开发特定治疗方法的努力变得复杂。典型纤毛病被称为Joubert综合征（JS），主要由CEP290基因突变引起。我们已经创建了一种JS小鼠模型，它比任何其他模型都更接近于人类的情况，并且在测试从患病肾脏分离的肾细胞时，发现了一种以前未被发现的肾脏异常，该异常对药物治疗有积极反应。我们的建议侧重于确定涉及纤毛病复杂表现的因素，以回答为什么携带同一基因突变的患者表现出不同的症状以及他们是否需要不同的治疗方法？为此，我们将把JS突变小鼠与不同品系的小鼠杂交，以模仿人类的遗传复杂性（注意，实验室小鼠是近亲繁殖的，而人类是近亲繁殖的），从而使小鼠具有一系列疾病严重程度。在这个相对简单的系统中，将有可能确定影响疾病严重程度的因素。除了对纤毛病领域的具体益处外，该提案还将展示利用小鼠遗传学了解复杂人类疾病的潜力。该项目可能为遗传性纤毛病患者提供长期利益，因为它以切实可行的方式提出了个性化医疗和个性化治疗的前景。具体来说，本研究建议的发现将有助于分类和准确诊断特定形式的纤毛病。同时，我们将评估针对这些特定形式的新的潜在治疗方法。事实上，我们已经确定了一种可以恢复JS肾细胞正常功能的药物，这表明下一轮的研究将朝着减少与纤毛病相关的发病率和死亡率的治疗迈出重要的一步，并减少受影响患者对透析和移植的需求。

Cystic kidney disease accounts for 10% of the 40,000 UK patients requiring renal replacement therapy (dialysis and transplantation). Cystic kidney disease is part of a group of disorders referred to as the "ciliopathies" that cause various combinations of cystic kidney disease, retinal degeneration and brain abnormalities in patients. There are no current disease modifying treatments for these conditions.The term "ciliopathy" covers a broad spectrum of disorders and patients typically can show a wide range of symptoms. For example, a mutation within the same gene can cause different symptoms in different individual patients. Clearly this complicates efforts to understand the cause of the disease, make accurate diagnoses, and develop specific treatments.The archetypal ciliopathy is known as Joubert Syndrome (JS) which is predominantly caused by mutations in the CEP290 gene. We have created a mouse model of JS that more closely resembles the human condition than any other and have identified a previously unrecognized abnormality in the kidney that responds positively to drug treatment when we test kidney cells that have been isolated from diseased kidneys.Our proposal focuses on identifying the factors involved in the complex presentation of ciliopathies to answer the question of why patients carrying mutations in the same gene show different symptoms and if they require different treatments?To do this, we will breed our JS mutant mice with a different strain of mouse to mimic the genetic complexity of humans (note laboratory mice are inbred, whilst humans are outbred) to give mice with a range of disease severity. In this relatively simple system, it will be possible to identify the factors that affect disease severity. In addition to the specific benefits to the field of ciliopathies, this proposal will provide a demonstration of the potential of using mouse genetics to understand complex human diseases in general. This project is likely to provide long-term benefit to patients with inherited ciliopathies as it brings forward in a tangible way the prospect of personalized medicine and individualized treatments for patients. Specifically, the findings of this research proposal will help to categorize and precisely diagnose specific forms of cliliopathy. In parallel, we will assess novel potential treatments tailored to these specific forms. The fact that we have already identified one drug that can restore normal function to JS kidney cells suggests that this next round of research will make a significant step towards a treatment to reduce the morbidity and mortality associated with ciliopathies and reduce the need for dialysis and transplantation in affected patients.