Delivery of a Myostatin Inhibitor by AAV Gene Therapy for Muscular Dystrophy

通过 AAV 基因疗法递送肌肉生长抑制素抑制剂治疗肌营养不良症

• 批准号: 7275480
• 负责人: Amanda Haidet-Phillips
• 金额: $ 3.08万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7275480
• 关键词: Actins; Adrenal Cortex Hormones; Adverse effects; Affect; Amyotrophic Lateral Sclerosis; Birth; Cardiac; Cataract; Clinical Trials; Complex; Cytoskeletal Proteins; Cytoskeleton; Defect; Delayed Puberty; Dependency; Dependovirus; Disease; Dose; Duchenne muscular dystrophy; Dystrophin; Extracellular Matrix; Fibrosis; Follistatin; Genes; Germ Cells; Heart failure; Hemophilia B; Hereditary Disease; Hypertension; Incidence; Injection of therapeutic agent; Intramuscular; Knowledge; Life; Liver; Longevity; Mediating; Medical; Methods; Morbidity - disease rate; Muscle; Muscle Weakness; Muscular Dystrophies; Mutation; Myocardium; Myopathy; Natural regeneration; Numbers; Other Therapy; Pathology; Patients; Play; Portal vein structure; Proteins; Rate; Respiratory Muscles; Respiratory Tract Infections; Role; Site; Skeletal system; Standards of Weights and Measures; Steroids; Systemic Therapy; Teenagers; Therapeutic; Therapeutic Effect; Thinking; Virus; Weight Gain; Wheelchairs; adeno-associated viral vector; bone loss; gene therapy; improved; inhibitor/antagonist; male; mdx mouse; mortality; mouse model; muscle regeneration; muscle strength; myostatin; pre-clinical; repaired; success

DESCRIPTION (provided by applicant): Duchenne's muscular dystrophy (DMD) affects 1 in 3500 live male births. DMD is characterized byprogressive muscle weakness and degeneration often leading to wheelchair dependency in the early teens. Mortality is usually a result of respiratory infection complicated by cardiac failure and most often occurs in late teens or early twenties. It is disappointing that despite tremendous medical advances, the lifespan of the DMD patient has not been significantly improved. There is no known cure and few new successful therapies have been added to the standard treatment repertoire. Overall, the high incidence (1/3500) of DMD, early morbidity and mortality, and lack of effective treatments provide urgent reasons to find other therapies. With the realization that structural defects in DMD will be very difficult to repair given that the defective protein dystrophin is normally part of a large and complex structural network, new thoughts have emerged which focus on muscle regeneration and reduced fibrosis. These 'muscle booster genes' encode for proteins that promote survival and regeneration of the compromised muscles. Myostatin inhibitors in particular have shown great promise and early pre-clinical signs for success. Additionally, adeno-associated virus (AAV)-mediated gene therapy has demonstrated potential for treating a number of genetic disorders. However, without a means of systemic delivery of AAV, the therapeutic effects of gene therapy will never reach cardiac and respiratory muscles needed to avoid problems that are the major causes for mortality in MD patients. Therefore, we propose to determine the optimal delivery method of an AAV vector encoding a secreted myostatin inhibitor by comparing intramuscular versus portal vein delivery in a mouse model of DMD, the dystrophin deficient mdx mouse. By optimizing a delivery method of a secreted myostatin inhibitor either to muscle or liver, we may ultimately gain a systemic therapy suitable for long-term therapy in DMD. Our Specific Aims are: 1. To determine whether intramuscular or portal vein delivery of AAV1 expressing the secreted myostatin inhibitor, follistatin, enhances muscle strength and coordination in the mdx mouse model of DMD. 2. To determine whether intramuscular or portal vein delivery of AAV1 expressing the secreted myostatin inhibitor, follistatin, can reverse or delay the dystrophic muscle pathology in the mdx mouse.

描述（由申请人提供）：Duchenne的肌肉营养不良症（DMD）影响3500分之1。 DMD的特征是临床肌肉无力和变性通常会导致青少年早期的轮椅依赖。死亡率通常是由于心脏衰竭复杂的呼吸道感染而导致的，并且大多数发生在十几岁或20年代初。令人失望的是，尽管医疗的进展巨大，但DMD患者的寿命并未得到显着改善。没有已知的治疗方法，很少有新的成功疗法已添加到标准治疗库中。总体而言，DMD的高发病率（1/3500），早期发病率和死亡率以及缺乏有效治疗的迫切原因是寻找其他疗法的迫切原因。随着人们意识到，鉴于有缺陷的蛋白质肌营养不良蛋白通常是大型且复杂的结构网络的一部分，DMD中的结构缺陷将非常难以修复，因此出现了新思想，这些思想的重点是肌肉再生和纤维化减少。这些“肌肉增强基因”编码促进受损肌肉生存和再生的蛋白质。尤其是肌生抑制蛋白抑制剂，表现出了巨大的希望和早期的临床前迹象。此外，与腺相关病毒（AAV）介导的基因疗法已经显示出可能治疗多种遗传疾病的潜力。但是，如果没有全身递送AAV的手段，基因疗法的治疗作用将永远不会达到心脏和呼吸道肌肉，以避免避免MD患者死亡的主要原因。因此，我们建议通过比较DMD的小鼠模型（肌营养不良蛋白缺陷的MDX小鼠）中的肌肉内与门静脉递送来确定编码分泌的肌抑制剂抑制剂的AAV载体的最佳输送方法。通过优化分泌的肌生抑制蛋白抑制剂的递送方法，无论是肌肉还是肝脏，我们最终可能会获得适用于DMD长期治疗的全身疗法。 我们的具体目的是： 1。确定表达分泌的肌抑制剂抑制剂的肌内或门静脉输送是否会增强DMD MDX小鼠模型中的肌肉强度和协调性。 2。为了确定表达分泌的肌抑制剂抑制剂的肌内或门静脉递送是否可以逆转或延迟MDX小鼠中营养不良的肌肉病理学。