Adeno-associated virus gene therapy prevents progression of kidney disease in genetic models of nephrotic syndrome

• DOI: 10.1126/scitranslmed.abc8226
• Publication Date: 2023-08-09T17:58:40Z
• Authors: Wen Y. Ding; Valeryia Kuzmuk; Sarah Hunter; Abigail Lay; Bryony Hayes; Matthew Beesley; Ruth Rollason; Jennifer A. Hurcombe; Fern Barrington; Catrin Masson; William Cathery; Carl May; Jack Tuffin; Timothy Roberts; Geraldine Mollet; Colin J. Chu; Jenny McIntosh; Richard J. Coward; Corinne Antignac; Amit Nathwani; Gavin I. Welsh; Moin A. Saleem
• Keywords: Podocin; Albuminuria; Adeno-associated virus

Gene therapy for kidney diseases has proven challenging. Adeno-associated virus (AAV) is used as a vector gene targeting other organs, with particular success demonstrated in monogenic diseases. We aimed to establish the by disease of podocyte. The most common cause childhood genetic nephrotic syndrome mutations podocyte NPHS2 , encoding podocin. AAV-based rescue this defect human and mouse models disease. In vitro transduction studies identified AAV-LK03 serotype highly efficient transducer podocytes. AAV-LK03–mediated podocin mutant podocytes resulted functional vitro, AAV 2/9–mediated transfer both inducible knockout knock-in successful amelioration A prophylactic approach 2/9 before induction conditional mice improvements albuminuria, plasma creatinine, urea, cholesterol, histological changes, long-term survival. therapeutic 2 weeks after proteinuric improvement urinary albuminuria at days 42 56 induction, corresponding albumin. Therefore, we have AAV-mediated renal established tractable target approaches.