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

• Published in: Science translational medicine 2023-08, Vol.15 (708), p.1
• Main Authors: Ding, Wen Y, Kuzmuk, Valeryia, Hunter, Sarah, Lay, Abigail, Hayes, Bryony, Beesley, Matthew, Rollason, Ruth, Hurcombe, Jennifer A, Barrington, Fern, Masson, Catrin, Cathery, William, May, Carl, Tuffin, Jack, Roberts, Timothy, Mollet, Geraldine, Chu, Colin J, Mcintosh, Jenny, Coward, Richard J, Antignac, Corinne, Nathwani, Amit, Welsh, Gavin I, Saleem, Moin A
• Format: Article
• Language: English
• Subjects: Animal models; Children; Cholesterol; Creatinine; Gene therapy; Kidney diseases; Nephrotic syndrome; Plasma
• ISSN: 1946-6234; 1946-3242
• DOI: 10.1126/scitranslmed.abc822

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