PRECLINICAL TRIAL OF DECORIN IN FIBROTIC DISEASE

天然蛋白聚糖装饰素作为一种治疗人类纤维化疾病的药物具有很大的前景。纤维化疾病的标志是细胞外基质的积累。现在已经确定，细胞因子转化生长因子- β (tgf - β)的过度表达介导细胞外基质的积累。在体外，Decorin抑制tgf - β，当全身或体内基因治疗时，在几种纤维化疾病模型中导致细胞外基质的积累减少。将装饰素作为一种有效的治疗药物发展的主要障碍是生物活性材料的大规模生产。这个问题已经解决了。本提案的目标是利用独特的生产方法生产足够数量的高质量的decorin，并在已建立的大鼠肾纤维化疾病模型中充分测试其功效。第一阶段建议的具体目的如下：生产纯化的重组人decorin，没有先前纯化方法的变性步骤特征；2. 建立编码大鼠decorin的表达载体，并利用其产生必要的量以测试其在大鼠慢性肾小球肾炎模型中的疗效；和3。建立质量控制方法，并通过生物物理分析和体外生物试验评估批间差异。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，每年用于治疗终末期肾病的费用高达130亿美元。tgf - β的过量产生是治疗干预的目标。在纤维化疾病动物模型中，人decorin在抑制tgf - β过度表达方面具有治疗作用。该提案启动了针对开发decorin作为治疗药物的研究，以满足这一巨大的市场。

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.