Gene therapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney

Abstract

There are currently no effective therapies for progressive fibrotic diseases. Recent evidence has implicated overproduction of transforming growth factor–β1 (TGF–β1) as a major cause of tissue fibrosis. Furthermore, this evidence implies that inhibitors of TGF–β1 may be clinically useful as antifibrotic agents. The proteoglycan decorin is a known inhibitor of TGF–β1. In a rat model of glomerulonephritis we have shown that fibrosis is mediated by TGF–β1. We report here that transfer of decorin cDNA into rat skeletal muscle increases the amount of decorin messenger RNA and protein present in skeletal muscle and decorin protein present in kidney, where it has a marked therapeutic effect on fibrosis induced by glomerulonephritis. Transfected glomerulonephritic rats showed a significant reduction in levels of glomerular TGF–β1 mRNA and TGF–β1 protein, extracellular matrix accumulation and proteinuria. These results demonstrate the potential of gene therapy as a novel treatment for fibrotic diseases caused by TGF–β1.