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J Am Soc Nephrol. 2018 Sep;29(9):2287-2297. doi: 10.1681/ASN.2018040426. Epub 2018 Jul 5.

Efficient Gene Transfer to Kidney Mesenchymal Cells Using a Synthetic Adeno-Associated Viral Vector.

Author information

Division of Nephrology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri.
Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts; and.
Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear, Boston, Massachusetts.
Division of Nephrology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri;



After injury, mesenchymal progenitors in the kidney interstitium differentiate into myofibroblasts, cells that have a critical role in kidney fibrogenesis. The ability to deliver genetic material to myofibroblast progenitors could allow new therapeutic approaches to treat kidney fibrosis. Preclinical and clinical studies show that adeno-associated viruses (AAVs) efficiently and safely transduce various tissue targets in vivo; however, protocols for transduction of kidney mesenchymal cells have not been established.


We evaluated the transduction profiles of various pseudotyped AAV vectors expressing either GFP or Cre recombinase reporters in mouse kidney and human kidney organoids.


Of the six AAVs tested, a synthetic AAV called Anc80 showed specific and high-efficiency transduction of kidney stroma and mesangial cells. We characterized the cell specificity, dose dependence, and expression kinetics and showed the efficacy of this approach by knocking out Gli2 from kidney mesenchymal cells by injection of Anc80-Cre virus into either homozygous or heterozygous Gli2-floxed mice. After unilateral ureteral obstruction, the homozygous Gli2-floxed mice had less fibrosis than the Gli2 heterozygotes had. We observed the same antifibrotic effect in β-catenin-floxed mice injected with Anc80-Cre virus before obstructive injury, strongly supporting a central role for canonical Wnt signaling in kidney myofibroblast activation. Finally, we showed that the Anc80 synthetic virus can transduce the mesenchymal lineage in human kidney organoids.


These studies establish a novel method for inducible knockout of floxed genes in mouse mesangium, pericytes, and perivascular fibroblasts and are the foundation for future gene therapy approaches to treat kidney fibrosis.


chronic kidney disease; gene therapy; virology

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