Biglycan as a Therapeutic for Muscular Dystrophy

描述（由申请人提供）：本提案的总体目标是使用动物模型来测试biglycan作为肌肉萎缩症蛋白质治疗的功效。杜氏肌营养不良症（DMD）是一种遗传性疾病，大约每3500名男孩中就有1人患病。这些孩子通常在12岁时就得坐轮椅，很少能活过20岁出头。目前还没有有效的治疗方法来治疗DM0的潜在病理。杜氏症和许多其他肌肉营养不良症的分子发病机制可以追溯到肌肉细胞表面的一种特殊的蛋白质集合，称为肌营养不良蛋白相关蛋白复合物（DAPC）。肌营养不良蛋白的突变导致DAPC组织的破坏。由此导致的DAPC功能失效导致肌肉细胞损伤和损失。我们最近发现，细胞外基质分子biglycan在肌肉细胞表面表达，并通过不同的机制结合到DAPC的三种核心成分的外胞域：α -肌糖酐、α -肌糖酐和γ -肌糖酐。这些分子相互作用表明，biglycan可以桥接DAPC的组成亚复合物，从而从细胞外协调和稳定整个复合物。事实上，biglycan缺失（bgn-/o）小鼠表现出营养不良表型，表现为肌细胞膜减弱和细胞死亡。这些观察结果表明，当肌营养不良蛋白缺失时，biglycan可以作为一种治疗药物从细胞外方面稳定DAPC。因此，Biglycan代表了开发肌肉萎缩症治疗方法的新途径。重要的是，由于biglycan- dapc相互作用完全发生在细胞外，因此biglycan可以通过系统递送纯化的重组蛋白引入肌肉。该项目将利用独特的生产方法生产足够数量的高质量多糖。并对几种肌营养不良动物模型进行了疗效试验。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to use animal models to test the efficacy of biglycan as a protein therapeutic for muscular dystrophy. Duchenne's muscular dystrophy (DMD) is a heritable disease that affects approximately 1 in 3,500 boys. These children are usually wheelchair-bound by age 12 and rarely survive past their early twenties. There are currently no effective treatments for the underlying pathology of DM0. The molecular pathogenesis of Duchenne's and many other muscular dystrophies has been traced to a specialized ensemble of proteins at the muscle cell surface known as the dystrophin-associated protein complex (DAPC). Mutation of dystrophin leads to disruption in the organization of the DAPC. The resulting failure of DAPC function results in muscle cell damage and loss. We have recently discovered that the extracellular matrix molecule biglycan is expressed at the muscle cell surface and binds, by distinct mechanisms, to the ectodomains of three core constituents of the DAPC: alpha-dystroglycan, aipha-sarcoglycan and gamma-sarcoglycan. These molecular interactions indicate that biglycan can bridge the component subcomplexes of the DAPC and thus coordinate and stabilize the entire complex from outside the cell. Indeed, biglycan null (bgn-/o) mice display a dystrophic phenotype as evidenced by weakened muscle cell membranes and cell death. These observations suggest that biglycan could serve as a therapeutic to stabilize the DAPC from its extracellular aspect when dystrophin is absent. Biglycan thus represents a new path for developing therapies for muscular dystrophies. Importantly, since the biglycan-DAPC interactions are wholly extracellular, biglycan can be introduced to the muscle by systemic delivery of the purified recombinant protein. This program will utilize unique production methods to produce sufficient quantities of high quality biglycan, .and test efficacy in several animal models of muscular dystrophy.