Glycosyltransferase Therapy for Myopathies

描述（由申请人提供）：杜氏肌营养不良症（DMD）是一种由肌营养不良蛋白基因突变或缺失引起的X连锁肌病。DMD是一种常见的肌肉萎缩症，每5000个男孩中就有1个受到影响。DMD是一种严重的疾病，引起进行性肌肉萎缩，导致受影响个体的肌肉萎缩和过早死亡。 尽管在过去的20年里已经了解了DMD的遗传缺陷，但没有批准的治疗方法可以最终改变疾病的结果。我们率先开发了一种基于GALGT 2过表达的DMD新疗法，GALGT 2是一种编码糖基化酶的基因，该酶改变骨骼肌膜上的糖，以促进改善疾病的蛋白质的表达。这种方法在三种不同的肌营养不良症小鼠模型中显示出治疗效果，包括DMD的mdx小鼠模型，表明GALGT 2基因治疗可能适用于多种形式的疾病。GALGT2过表达还可以保护野生型肌肉免受损伤，因此可能具有超越神经肌肉疾病的治疗用途。鉴于这些证明治疗功效的概念验证研究，我们开发了用于人类临床试验的基因治疗载体。动脉内递送至后肢肌肉已经显示出在mdx小鼠中的功能校正和在非人灵长类动物中的持续表达。这项工作帮助我们实现了我们的目标，即进行DMD的第一个GALGT2基因治疗临床试验。 本文提出的工作将首次评估GALGT 2在保护心肌方面的治疗效果，心肌是一种极大地影响DMD发病率和死亡率的肌肉。它还将测试允许在骨骼肌和心脏中高表达的新一代AAV载体，以确定单剂量血管递送是否可用于治疗整个DMD患者。其次，它将在DMD的严重大型动物模型中测试GALGT2基因疗法。这解决了基因治疗对人类的可扩展性问题，并更严格地测试了其治疗价值。第三，它将描述一种调节内源性肌肉Galgt2基因表达的新途径，开辟了利用这一重要基因进行治疗开发的新方法。

DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD) is an X-linked myopathy caused by mutations or deletions in the dystrophin gene. DMD is a common form of muscular dystrophy, affecting about 1 in every 5000 boys. DMD is a severe disease, causing progressive muscle wasting that leads to loss of ambulation and premature death in affected individuals. Despite having understood the genetic defect in DMD for the past 20 years, no approved therapy exists that has been shown to ultimately alter disease outcome. We have pioneered the development of a novel therapy for DMD based on the overexpression of GALGT2, a gene that encodes a glycosylation enzyme that alters sugars on the skeletal muscle membrane in order to boost the expression of proteins that ameliorate disease. This approach has shown therapeutic efficacy in three different mouse models of muscular dystrophy, including the mdx mouse model for DMD, suggesting that GALGT2 gene therapy may be useful in multiple forms of the disease. GALGT2 overexpression can also protect wild type muscles from injury and may therefore have therapeutic usefulness that extends beyond neuromuscular disorders. In light of these proof of concept studies demonstrating therapeutic efficacy, we have developed gene therapy vectors for use in human clinical trials. Intra-arterial delivery to the hindlimb muscles has shown functional correction in the mdx mouse and sustained expression in the non-human primate. This work has helped move us toward our goal of performing the first GALGT2 gene therapy clinical trial for DMD. The work proposed here will, for the first time, assess the therapeutic efficacy of GALGT2 in protecting the heart muscle, a muscle that greatly affects DMD morbidity and mortality. It will also test a new generation AAV vector that allows high expression in both skeletal muscle and heart to determine if single dose vascular delivery can be used to treat the whole DMD patient. Second, it will test GALGT2 gene therapy in a severe large animal model of DMD. This addresses issues of the scalability of gene therapy to the human and more rigorously tests its therapeutic value. Third, it will describe a new pathway that regulates the expression of endogenous muscle Galgt2 gene expression, opening up new approaches to exploit this important gene for therapy development.