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

慢性肾脏疾病（CKD）影响了十分之一的成年人，每年花费NHS约14.5亿英镑。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。基因治疗可能为这些慢性肾病提供一个潜在的解决方案。然而，在体内用腺相关病毒（aav）转导足细胞或小管上皮细胞的成功程度有限。该项目旨在通过鉴定能够成功转导肾细胞的新型aav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，并识别那些最有效地转导肾细胞的血清型。aav将在单层培养物、肾类器官和体内进行筛选，以确定其物理和功能转导效果。一旦筛选出来，最有效的aav将被用作在体内和体外的遗传性肾脏疾病模型中纠正基因突变的载体，如关节挛裂-肾功能障碍-胆汁淤积（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.