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

Sci Transl Med. 2023 Aug 9;15(708):eabc8226. doi: 10.1126/scitranslmed.abc8226. Epub 2023 Aug 9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria
  • Animals
  • Dependovirus / genetics
  • Disease Models, Animal
  • Genetic Therapy / methods
  • Genetic Vectors
  • Humans
  • Kidney Diseases*
  • Mice
  • Mice, Knockout
  • Models, Genetic
  • Nephrotic Syndrome* / genetics
  • Nephrotic Syndrome* / therapy

Supplementary concepts

  • Adeno-associated virus-2