The natural proteoglycan decorin shows great promise as a therapy for human fibrotic diseases. The hallmark of fibrotic disease is accumulation of extracellular matrix. It is now well established that overexpression of the cytokine transforming growth factor-beta (TGF-beta) mediates accumulation of extracellular matrix. Decorin inhibits TGF-beta in vitro and, when administered systemically or by gene therapy in vivo, leads to decreased accumulation of extracellular matrix in several models of fibrotic disease. The major impediment to the development of decorin as an effective therapeutic has been large-scale production of biologically active material. This problem has been solved. The goal of this proposal is to use unique production methods to produce sufficient quantities of high quality decorin and to fully test its efficacy in well-established models of renal fibrotic disease in the rat. The specific aims of this Phase I proposal are as follows: 1. Produce recombinant human decorin purified without the denaturation step characteristic of previous purification methods; 2. Develop an expression vector encoding rat decorin and use it to generate quantities necessary to test its efficacy in a chronic model of glomerulonephritis in the rat; and 3. Establish quality control methods and assess batch to batch variation by biophysical analysis and in vitro biological assays. PROPOSED COMMERCIAL APPLICATIONS: Fibrotic diseases, which include end-stage renal disease (ESRD), are major causes of human suffering and death. It costs $13 billion a year to care for ESRD patients in the United States. Overproduction of TGF-beta is a target for therapeutic intervention. Human decorin is therapeutic in suppressing TGF-beta overexpression in animal models of fibrotic disease. This proposal initiates studies directed at developing decorin as a therapeutic to address this large market.
Thesaurus Terms: biotherapeutic agent, decorin, glomerulonephritis, method development, protein purification, recombinant protein collagen, epidermal growth factor, growth factor receptor, protein binding, transfection /expression vector, transforming growth factor, vaccinia virus mass tissue /cell culture
