Glycosyltransferase Therapy for Myopathies

描述(申请人提供)：Duchenne肌营养不良症(DMD)是一种X连锁肌病，由dystrophin基因突变或缺失引起。DMD是一种常见的肌肉营养不良症，大约每5000名男孩中就有一名患有DMD。DMD是一种严重的疾病，会导致进行性肌肉萎缩，导致患者丧失行走能力和过早死亡。尽管在过去的20年里已经了解了DMD的遗传缺陷，但还没有被证明最终改变疾病结果的被批准的治疗方法。我们率先开发了一种基于GALGT2过表达的DMD新疗法，GALGT2是一种编码糖基化酶的基因，可以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小鼠模型上显示了治疗效果，包括DMD的MDX小鼠模型，这表明GALGT2基因治疗可能对多种形式的疾病有用。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。根据这些证明疗效的概念研究，我们开发了用于人类临床试验的基因治疗载体。动脉内注射到后肢肌肉在MDX小鼠中显示出功能纠正，在非人类灵长类动物中持续表达。这项工作帮助我们朝着执行第一个针对DMD的GALGT2基因治疗临床试验的目标前进。这里提出的工作将首次评估GALGT2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。它还将测试新一代AAV载体，该载体允许在骨骼肌和心脏中高表达，以确定是否可以使用单剂血管输送来治疗整个DMD患者。其次，它将在一个严重的DMD大型动物模型中测试GALGT2基因治疗。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，为开发这一重要基因治疗开发开辟新的途径。

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.