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

Wen Y. Ding, Valeryia Kuzmuk, Abigail Lay, Bryony Hayes, 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*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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.
Original languageEnglish
Article numbereabc8226
Pages (from-to)eabc8226
JournalScience Translational Medicine
Issue number708
Publication statusPublished - 9 Aug 2023

Bibliographical note

Funding Information:
Many thanks to K. Stevenson and K. Burt, who processed the plasma and urine samples. Flow cytometry was run with the help of L. Suiero Ballesteros and A. Herman. We gratefully acknowledge the Wolfson Bioimaging Facility, particularly A. Leard and K. Jepson, for support and assistance in this work. W.Y.D. was funded by the Wellcome Trust/ Elizabeth Blackwell Institute Clinical Primer Scheme, Kidney Research U.K. Clinical Research Training Fellowship (TF7/2015 to W.Y.D.), and the NIHR as an academic clinical lecturer. This work was also funded by the Nephrotic Syndrome Trust, grant awards SGL024\1045 from the Academy of Medical Sciences to W.Y.D., grant awards ST_004_20151126 and KKR/Paed 2016/01 from Kidney Research UK to G.I.W., and MR/R003017/1 from the Medical Research Council to M.A.S. R.J.C. was supported by an MRC Senior Research Fellowship (MR/K010492/1).

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Copyright © 2023 The Authors, some rights reserved.


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