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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：
9038431
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/9038431
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 Health 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 Recombinant adeno-associated virus (rAAV)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 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.