Understanding and treating kidney disease in arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome

慢性肾脏疾病(CKD)影响着每10个成年人中的1个，每年花费NHS约14.5亿GB。一些CKD病例是由于基因突变影响肾小管上皮细胞或肾滤过屏障的足细胞的生物学，导致肾功能丧失，患者需要透析或移植。基因治疗可以为这些CKD病例提供一种潜在的解决方案。然而，在体中用腺相关病毒(AAVs)转导足细胞或肾小管上皮细胞的研究成果有限。该项目旨在通过鉴定新的能够成功转导肾脏细胞的AAVs来解决这一问题。这将使用一种试剂盒来完成，该试剂盒允许我们同时筛选70种不同的AAV血清型，并识别哪些最有效地转导肾脏细胞。AAVs将在单层培养、肾脏器官和体内进行筛选，以确定其物理和功能转导效率。一旦经过筛选，最有效的AAVs将被用作载体，在体内和体外遗传性肾脏疾病模型中纠正遗传突变，如关节旋转-肾功能障碍-胆汁淤积症(ARC)综合征。

Chronic Kidney Disease (CKD) affects 1 in 10 adults and costs the NHS approximately £1.45 billion annually. Some cases of CKD are due to genetic mutations which affect the biology of kidney tubular epithelial cells or podocytes of the kidney filtration barrier, resulting in a loss of kidney function and patients requiring dialysis or transplantation. Gene therapy could provide a potential solution for these cases of CKD. However, there has been limited success transducing podocytes or tubular epithelial cells with adeno-associated viruses (AAVs) in vivo. This project aims to address this by identifying new AAVs which can successfully transduce kidney cells. This will be done using a kit which allows us to screen 70 AAV different serotypes simultaneously and identify those which transduce kidney cells most effectively. The AAVs will be screened both in monolayer cultures, kidney organoids and in-vivo to determine both their physical and functional transduction efficacies. Once screened, the most effective AAVs will be used as vectors to correct a genetic mutation in both in vivo and in vitro disease models of genetic renal diseases such as arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome.