Models, modifiers and novel treatments of Joubert syndrome

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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.