Treatment of Duchenne Muscular Dystrophy with the Muscle Calcium Pump

用肌肉钙泵治疗杜氏肌营养不良症

基本信息

批准号：
9546395
负责人：
Dongsheng Duan
金额：
$ 61.65万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9546395
关键词：
Accelerometer Adolescent Adult Affect Animal Model Autopsy Biological Assay Biopsy Ca(2+)-Transporting ATPase Calcium Canis familiaris Cell Death Clinical Trials Codon Nucleotides Dependovirus Disease Duchenne muscular dystrophy Echocardiography Electrocardiogram Endoplasmic Reticulum Event Excision Forelimb Foundations Future Gene Transfer Goals Heart Heart Diseases Hindlimb Histology Homeostasis Human In Situ Injections Intravenous Lead Limb structure Link Magnetic Resonance Imaging Mammals Mediating Methods Modeling Molds Monitor Mus Muscle Muscle Cells Muscle function Muscular Dystrophies Myocardium Myopathy Necrosis Pathogenicity Patients Proteolysis Protocols documentation Quality of life Reproducibility Safety Sarcoplasmic Reticulum Skeletal Muscle Tail Technology Transfer Testing Therapeutic Time Toxic effect Translating Treatment Efficacy Tyrosine Veins adeno-associated viral vector animal data gait examination gene therapy grasp heart function immunoreaction improved improved functioning intravenous injection mdx mouse novel therapeutics phase I trial pre-clinical protein degradation restoration vector

项目摘要

Project Abstract Cytosolic calcium overload is a pivotal pathogenic mechanism in Duchenne muscular dystrophy (DMD), a lethal debilitating muscle disease. Elevated cytosolic calcium triggers proteolysis and muscle cell death. Sarco/endoplasmic reticulum calcium ATPase 2a (SERCA2a) is the calcium pump that removes cytosolic calcium in both skeletal and cardiac muscle. Unfortunately, the SERCA2a level is reduced in DMD muscle. Enhancing SERCA2a expression may restore cytosolic calcium homeostasis and reduce muscle disease in DMD. To explore this novel therapy, we generated an adeno-associated viral vector (AAV) to express SERCA2a. We injected the AAV SERCA2a vector via the tail vein to mdx mice, the most commonly used DMD model. Treatment significantly improved skeletal muscle force and heart function. To translate our findings to large mammals, we propose to test AAV SERCA2a therapy in symptomatic DMD dogs, the best large animal model for DMD. We hypothesize that AAV SERCA2a therapy can significantly enhance cytosolic calcium removal and ameliorate skeletal muscle and heart disease in dystrophic dogs. To test this hypothesis, we will pursue two specific aims. In our first aim, we will test whether regional AAV SERCA2a therapy can ameliorate limb muscle disease and improve function. Regional therapy holds potential to improve the life quality of patients, especially these at late-stage. In our second aim, we will test whether systemic AAV SERCA2a therapy can lead to bodywide improvement in affected dogs. DMD affects all muscles in the body. Whole body muscle therapy will result in maximal protection. In summary, our proposed studies will generate the critical large animal data for a future human trial.

项目摘要细胞溶质钙超载是杜氏肌营养不良症 (DMD) 的关键致病机制。致命的肌肉衰弱疾病。胞浆钙升高会引发蛋白水解和肌肉细胞死亡。肌浆/内质网钙 ATP 酶 2a (SERCA2a) 是去除细胞质的钙泵骨骼肌和心肌中的钙。不幸的是，DMD 肌肉中的 SERCA2a 水平降低。增强 SERCA2a 表达可能会恢复细胞质钙稳态并减少肌肉疾病 DMD。为了探索这种新疗法，我们生成了腺相关病毒载体（AAV）来表达 SERCA2a。我们通过尾静脉将 AAV SERCA2a 载体注射到 mdx 小鼠中，这是最常用的 DMD 模型。治疗显着改善了骨骼肌力量和心脏功能。翻译我们的根据大型哺乳动物的研究结果，我们建议在有症状的 DMD 狗中测试 AAV SERCA2a 疗法，这是最好的 DMD 大型动物模型。我们假设 AAV SERCA2a 疗法可以显着增强细胞质去除钙并改善营养不良的狗的骨骼肌和心脏病。为了检验这个假设，我们将追求两个具体目标。在我们的第一个目标中，我们将测试区域 AAV SERCA2a 疗法是否可以改善肢体肌肉疾病，提高功能。局部治疗有改善生活的潜力患者的质量，尤其是晚期患者的质量。在我们的第二个目标中，我们将测试系统性 AAV 是否 SERCA2a 疗法可以使受影响的狗全身得到改善。 DMD 影响身体的所有肌肉。全身肌肉治疗将带来最大程度的保护。总之，我们提出的研究将产生未来人体试验的关键大型动物数据。