PRECLINICAL TRIAL OF DECORIN IN FIBROTIC DISEASE

天然的蛋白多糖核心蛋白在治疗人类纤维性疾病方面显示出巨大的潜力。纤维性疾病的特点是细胞外基质堆积。现已证实，细胞因子转化生长因子-β的过度表达介导了细胞外基质的积聚。核心蛋白聚糖在体外抑制转化生长因子-β，当系统给药或通过体内基因治疗时，在几种纤维化疾病模型中导致细胞外基质积聚减少。核心蛋白聚糖作为一种有效的治疗药物，其发展的主要障碍是生物活性物质的大规模生产。这个问题已经解决了。这项提议的目标是使用独特的生产方法来生产足够数量的高质量核心蛋白聚糖，并在大鼠肾脏纤维化疾病的成熟模型中充分测试其疗效。拟议的商业应用：纤维化疾病，包括终末期肾病(ESRD)，是人类痛苦和死亡的主要原因。在美国，照顾ESRD患者每年要花费130亿美元。转化生长因子-β的过度产生是治疗干预的一个靶点。人核心蛋白聚糖在抑制纤维化疾病动物模型中的转化生长因子-β的过度表达方面具有治疗作用。这项提议启动了旨在开发核心蛋白的研究，作为一种治疗手段，以满足这一巨大市场的需求。

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.