title: Combined paracrine and endocrine AAV9 mediated expression of hepatocyte growth factor for the treatment of renal fibrosis.
abstract: In chronic renal disease, tubulointerstitial fibrosis is a leading cause of renal failure. Here, we made use of one of the most promising gene therapy vector platforms, the adeno-associated viral (AAV) vector system, and the COL4A3-deficient mice, a genetic mouse model of renal tubulointerstitial fibrosis, to develop a novel bidirectional treatment strategy to prevent renal fibrosis. By comparing different AAV serotypes in reporter studies, we identified AAV9 as the most suitable delivery vector to simultaneously target liver parenchyma for endocrine and renal tubular epithelium for paracrine therapeutic expression of the antifibrogenic cytokine human hepatocyte growth factor (hHGF). We used transcriptional targeting to drive hHGF expression from the newly developed CMV-enhancer-Ksp-cadherin-promoter (CMV-Ksp) in renal and hepatic tissue following tail vein injection of rAAV9-CMV-Ksp-hHGF into COL4A3-deficient mice. The therapeutic efficiency of our approach was demonstrated by a remarkable attenuation of tubulointerstitial fibrosis and repression of fibrotic markers such as collagen1alpha1 (Col1A1), platelet-derived growth factor receptor-beta (PDGFR-beta), and alpha-smooth muscle actin (SMA). Taken together, our results show the great potential of rAAV9 as an intravenously applicable vector for the combined paracrine and endocrine expression of antifibrogenic factors in the treatment of renal failure caused by tubulointerstitial fibrosis.
authors.affiliation: Institute for Pathology, University of Cologne, Cologne, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schievenbusch
authors.forename: Ingo
authors.initials: I
authors.lastname: Strack
authors.forename: Melanie
authors.initials: M
authors.lastname: Scheffler
authors.forename: Roswitha
authors.initials: R
authors.lastname: Nischt
authors.forename: Oliver
authors.initials: O
authors.lastname: Coutelle
authors.forename: Marianna
authors.initials: M
authors.lastname: Hösel
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.forename: Jochen W U
authors.initials: JW
authors.lastname: Fries
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Dienes
authors.forename: Margarete
authors.initials: M
authors.lastname: Odenthal
authors.forename: Hildegard
authors.initials: H
authors.lastname: Büning
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics; D024141:Collagen Type IV / Q000172:deficiency / Q000235:genetics; D000229:Dependovirus / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics / Q000502:physiology; D005355:Fibrosis / Q000628:therapy*; D005786:Gene Expression Regulation; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000628:therapy*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D014161:Transduction, Genetic
chemical_list: D001324:Autoantigens; D024141:Collagen Type IV; C057112:type IV collagen alpha3 chain; D017228:Hepatocyte Growth Factor