| First Author | Ding WY | Year | 2023 |
| Journal | Sci Transl Med | Volume | 15 |
| Issue | 708 | Pages | eabc8226 |
| PubMed ID | 37556557 | Mgi Jnum | J:343538 |
| Mgi Id | MGI:7567531 | Doi | 10.1126/scitranslmed.abc8226 |
| Citation | Ding WY, et al. (2023) Adeno-associated virus gene therapy prevents progression of kidney disease in genetic models of nephrotic syndrome. Sci Transl Med 15(708):eabc8226 |
| abstractText | 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. |
