Therapeutic potential for AAV/micro-dystrophin transfer to cardiopulmonary tissue

AAV/微肌营养不良蛋白转移至心肺组织的治疗潜力

基本信息

批准号：
8885593
负责人：
JEFFREY S CHAMBERLAIN
金额：
$ 50.39万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8885593
关键词：
Accounting Adrenal Cortex Hormones Affect Animals Becker Muscular Dystrophy Biological Assay Biological Preservation Breathing Canis familiaris Cardiac Cardiopulmonary Catheters Cephalic Cessation of life Child Clinical Trials Collaborations Complementary DNA Cytotoxic T-Lymphocytes DNA DNA Vaccines Disease Duchenne muscular dystrophy Dystrophin Fibrosis Forelimb Functional disorder Future Gene Transfer Genes Goals Heart Heart failure Hereditary Disease Histopathology Human Immune Immune response Immunosuppression Inborn Genetic Diseases Injury Integrated Delivery Systems Intercostal Muscles Libraries Limb structure Link Longevity Measures Mechanics Mediating Methodology Methods Modeling Monitor Morphology Mus Muscle Muscle function Mutant Strains Mice Mutation Myocardial dysfunction Myocardium Operative Surgical Procedures Pathology Patients Pharmaceutical Preparations Phenotype Production Property Proteins Protocols documentation Regulator Genes Resistance development Respiratory Diaphragm Respiratory Failure Respiratory Muscles Skeletal Muscle Striated Muscles Testing Therapeutic Tissues Translating Treatment Efficacy Vaccination Vaccines Viral Work adeno-associated viral vector design efficacy testing gene therapy hemodynamics improved mature animal mdx mouse micro-dystrophin muscle form mutant novel older patient patient population prevent public health relevance respiratory therapy development treatment strategy vector

项目摘要

DESCRIPTION (provided by applicant): Duchenne and Becker muscular dystrophies (DMD/BMD) are X-linked recessive genetic disorders caused by mutations in the dystrophin gene. DMD is among the most common lethal inherited disorder of children, but finding a cure remains an elusive goal. Improved treatment approaches using surgery, corticosteroids, respiratory support and heart medication are leading to increases in lifespan. While most patients previously died of respiratory failure due to weakness of the diaphragm and intercostal muscles, a shift has been observed to an increasingly older patient population dying of respiratory or heart failure. Nonetheless, most treatment strategies for DMD/BMD are focused on limb muscles, despite evidence that skeletal muscle rescue can exacerbate cardiac dysfunction. Our lab has shown that adeno-associated viral (AAV) vectors can efficiently target both skeletal and cardiac muscles in mouse (mdx) and canine models for DMD, and that systemic AAV delivery of micro-dystrophin cassettes can halt progressive dystrophic changes and significantly improve diaphragm and cardiac function in mdx mice. Functional rescue, while impressive, is incomplete and recent studies suggest multiple ways to improve the functionality and muscle-specific expression of micro-dystrophin. Testing and comparing these modified micro-dystrophins is complicated by the mildness of the mdx mouse phenotype, so we propose to use a more severely affected mdx4cv/Dba-2 mutant that displays extensive cardiorespiratory fibrosis and a more progressive pathology. These cassettes will comprise both new microdystrophin cDNAs and new gene regulatory cassettes optimized for expression and function in respiratory and cardiac muscle following systemic AAV-mediated gene transfer to adult animals. We will also integrate these delivery systems in the context of strategies designed to prevent immune-mediated loss of dystrophin expression. These include a novel reverse vaccine protocol designed to induce tolerance, and transient immune suppression. Together these approaches could significantly impact the ability to treat respiratory and cardiac muscles of DMD patients. This work also has broad implications for gene therapy of other disorders involving cardiopulmonary dysfunction.

描述（由申请人提供）：杜氏肌营养不良症和贝克尔肌营养不良症 (DMD/BMD) 是由肌营养不良蛋白基因突变引起的 X 连锁隐性遗传病，是最常见的儿童致命遗传性疾病之一，但找到治愈方法仍然是一个难题。使用手术、皮质类固醇、呼吸支持和心脏药物的改进治疗方法正在延长寿命，而大多数患者以前因呼吸衰竭而死亡。然而，尽管有证据表明骨骼肌救援会加剧心脏功能障碍，但大多数 DMD/BMD 治疗策略都集中在肢体肌肉上。实验室已表明，腺相关病毒 (AAV) 载体可以有效地靶向小鼠 (mdx) 和犬 DMD 模型中的骨骼肌和心肌，并且微肌营养不良蛋白的系统性 AAV 递送盒式磁带可以阻止 mdx 小鼠的进行性营养不良变化并显着改善膈肌和心脏功能，虽然功能性挽救令人印象深刻，但并不完整，最近的研究提出了多种方法来改善微肌营养不良蛋白的功能和肌肉特异性表达。微抗肌营养不良蛋白因 mdx 小鼠表型的温和性而变得复杂，因此我们建议使用严重受影响的 mdx4cv/Dba-2 突变体，该突变体表现出广泛的心肺功能这些盒将包含新的微肌营养不良蛋白 cDNA 和新的基因调控盒，这些盒针对 AAV 介导的全身性基因转移到成年动物后在呼吸和心肌中的表达和功能进行了优化。旨在防止免疫介导的肌营养不良蛋白表达丧失的策略背景，其中包括旨在诱导耐受性的新型反向疫苗方案，以及短暂的免疫抑制，这些方法可以显着影响治疗 DMD 的呼吸和心肌的能力。这项工作对于涉及心肺功能障碍的其他疾病的基因治疗也具有广泛的意义。