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双糖链蛋白聚糖作为肌营养不良症的蛋白质治疗剂的功效。杜兴氏肌营养不良症（DMD）是一种遗传性疾病，大约每3,500个男孩中就有1个受到影响。这些儿童通常在12岁之前就坐轮椅，很少能活过20岁出头。目前还没有有效的治疗DM 0的潜在病理学。杜氏肌营养不良症和许多其他肌营养不良症的分子发病机制已经追溯到肌细胞表面的一种专门的蛋白质集合，称为肌营养不良蛋白相关蛋白复合物（DAPC）。抗肌萎缩蛋白的突变导致DAPC组织的破坏。DAPC功能的失败导致肌肉细胞损伤和损失。我们最近发现，细胞外基质分子双糖蛋白聚糖在肌肉细胞表面表达，并通过不同的机制与DAPC的三种核心成分的胞外域结合：α-肌营养不良聚糖、α-肌聚糖和γ-肌聚糖。这些分子相互作用表明，双糖链聚糖可以桥接DAPC的组分亚复合物，从而从细胞外协调和稳定整个复合物。事实上，双糖蛋白聚糖缺失（bgn-/o）小鼠表现出营养不良的表型，这一点可以通过肌肉细胞膜变弱和细胞死亡来证明。这些观察结果表明，双糖链蛋白聚糖可以作为一种治疗剂，以稳定DAPC从其细胞外方面时，肌营养不良蛋白是不存在的。因此，Biglycan代表了开发肌营养不良症疗法的新途径。重要的是，由于双糖蛋白聚糖-DAPC相互作用完全是细胞外的，因此可以通过纯化的重组蛋白的全身递送将双糖蛋白聚糖引入肌肉。该项目将利用独特的生产方法生产足够数量的高质量双糖链蛋白聚糖，并在几种肌营养不良症动物模型中测试功效。

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.