Adeno-associated virus-based gene therapy treats inflammatory kidney disease in mice

• Published in: The Journal of clinical investigation Vol. 134; no. 17; pp. 1 - 12
• Main Authors: Wu, Guochao, Liu, Shuya, Hagenstein, Julia, Alawi, Malik, Hengel, Felicitas E, Schaper, Melanie, Akyüz, Nuray, Liao, Zhouning, Wanner, Nicola, Tomas, Nicola M, Failla, Antonio Virgilio, Dierlamm, Judith, Körbelin, Jakob, Lu, Shun, Huber, Tobias B
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.09.2024
• Subjects: Animals; Anti-Glomerular Basement Membrane Disease - genetics; Anti-Glomerular Basement Membrane Disease - immunology; Anti-Glomerular Basement Membrane Disease - therapy; Antibodies; Basement membranes; Care and treatment; Clinical trials; Dependovirus - genetics; Dependoviruses; Diseases; Efficiency; Endothelial cells; Endothelial Cells - metabolism; Gene therapy; Gene transfer; Genes; Genetic disorders; Genetic research; Genetic Therapy - methods; Genetic Vectors - genetics; Germany; Glomerulonephritis; Glomerulonephritis - genetics; Glomerulonephritis - immunology; Glomerulonephritis - therapy; Glomerulus; Health aspects; Humans; Inflammation; Kidney diseases; Kidney Glomerulus - pathology; Medical research; Medicine, Experimental; Mice; Peptides; Physiological aspects; Serotypes; Tropism; Viral antibodies; Germany; Nephrology; Autoimmune diseases; Gene therapy; Endothelial cells; Therapeutics
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI174722

Adeno-associated virus (AAV) is a promising in vivo gene delivery platform showing advantages in delivering therapeutic molecules to difficult or undruggable cells. However, natural AAV serotypes have insufficient transduction specificity and efficiency in kidney cells. Here, we developed an evolution-directed selection protocol for renal glomeruli and identified what we believe to be a new vector termed AAV2-GEC that specifically and efficiently targets the glomerular endothelial cells (GEC) after systemic administration and maintains robust GEC tropism in healthy and diseased rodents. AAV2-GEC-mediated delivery of IdeS, a bacterial antibody-cleaving proteinase, provided sustained clearance of kidney-bound antibodies and successfully treated antiglomerular basement membrane glomerulonephritis in mice. Taken together, this study showcases the potential of AAV as a gene delivery platform for challenging cell types. The development of AAV2-GEC and its successful application in the treatment of antibody-mediated kidney disease represents a significant step forward and opens up promising avenues for kidney medicine.