Kidney Week

Abstract: SA-OR057

Adeno-Associated Virus Gene Therapy Prevents Progression of Kidney Disease in Genetic Human and Mouse Models of Nephrotic Syndrome

Session Information

• Glomerular Diseases: Technologies, Mechanisms, and Therapeutics
  November 09, 2019 | Location: 201, Walter E. Washington Convention Center
  Abstract Time: 06:18 PM - 06:30 PM

Category: Glomerular Diseases

• 1204 Podocyte Biology

Authors

• Ding, Wen Yi, University of Bristol, Bristol, United Kingdom

Wen Yi Ding, MBBS

• Hunter, Sarah, University of Bristol, Bristol, United Kingdom

Sarah Hunter,

• Lay, Abigail Charlotte, University of Bristol, Bristol, United Kingdom

Abigail Charlotte Lay,

• Hayes, Bryony, University of Bristol, Bristol, United Kingdom

Bryony Hayes,

• Kuzmuk, Valeryia, University of Bristol, Bristol, United Kingdom

Valeryia Kuzmuk,

• Beesley, Matthew Frederick, NHS, Cheltenham, Gloucestershire, United Kingdom

Matthew Frederick Beesley,

• Hurcombe, Jenny, University of Bristol, Bristol, United Kingdom

Jenny Hurcombe,

• Barrington, Fern, University of Bristol, Bristol, United Kingdom

Fern Barrington,

• Masson, Catrin, University of Bristol, Bristol, United Kingdom

Catrin Masson,

• Mollet, Geraldine, Inserm U1163, Paris, France

Geraldine Mollet,

• Chu, Colin J., University of Bristol, Bristol, United Kingdom

Colin J. Chu,

• Coward, Richard, University of Bristol, Bristol, United Kingdom

Richard Coward,

• Antignac, Corinne, Imagine Institute/Laboratory of Hereditary Kidney Diseases, Paris, France

Corinne Antignac,

• Welsh, Gavin Iain, University of Bristol, Bristol, United Kingdom

Gavin Iain Welsh,

• Saleem, Moin, University of Bristol, Bristol, United Kingdom

Moin Saleem,

Background

Gene therapy targeting the kidney has proven challenging thus far. Adeno-Associated Virus (AAV) has been used successfully for gene therapy targeting other organs, with particular success demonstrated in targeting monogenic diseases. Here we aimed to advance gene therapy in the kidney by targeting a monogenic disease of the kidney. The commonest cause of genetic nephrotic syndrome in children is a mutation in NPHS2 encoding podocin. Here, AAV-mediated gene therapy was tested on a conditional podocin knock-out mouse model (iPod NPHS2^fl/fl), and on human podocytes with the commonest podocin mutation, R138Q.

Methods

AAV 2/9 expressing mouse podocin with a podocyte-specific promoter (either a mouse or human nephrin promoter) was delivered via tail vein injection to iPod NPHS2^fl/fl. AAV serotypes LK03 and 2/9 were used to transduce immortalised human kidney cell lines to test for transduction efficiency. AAV LK03 expressing human podocin with a minimal nephrin promoter was used to transduce immortalised R138Q podocin mutant human podocytes.

Results

AAV 2/9 expressing podocin demonstrated successful transduction of podocytes in iPod NPHS2^fl/fl. Treated mice showed a significant improvement in urinary albumin creatinine ratio (n=9/group, p<0.001 at day 42) and prolonged survival (n=3-4/group, p=0.049). In vitro, AAV LK03 transduced the human podocyte with a transduction efficiency of close to 100%. Transduction of the R138Q podocin mutant human podocyte with AAV LK03 expressing podocin demonstrated functional rescue in vitro.

Conclusion

This is the first study demonstrating successful gene transfer using AAV 2/9 in a monogenic kidney disease in a mouse model. AAV LK03 demonstrated highly efficient transduction of the human podocyte, making it a promising potential serotype for translation of gene therapy targeting the podocyte.

Funding

• Private Foundation Support