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：
9237306
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/9237306
关键词：
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 DBA/2 Mouse DNA DNA Vaccines Development 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 Intercostal Muscles Libraries Limb structure Link Longevity Measures 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 Proteins Protocols documentation Recombinant adeno-associated virus (rAAV)Regulator Genes Resistance Respiratory Diaphragm Respiratory Failure Respiratory Muscles Skeletal Muscle Striated Muscles System Testing Therapeutic Tissues Translating Treatment Efficacy Vaccination Vaccines Viral Work adeno-associated viral vector design efficacy testing gene therapy hemodynamics improved improved functioning mature animal mdx mouse mechanical properties micro-dystrophin muscle form mutant novel older patient patient population prevent public health relevance recessive genetic trait 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（由应用提供）：Duchenne和Becker肌肉营养不良（DMD/BMD）是由肌营养不良蛋白基因突变引起的X连锁隐性遗传疾病。 DMD是最常见的致命遗传儿童疾病之一，但找到治愈仍然是一个难以捉摸的目标。使用手术，皮质类固醇，呼吸支持和心脏药物的治疗方法改善了治疗方法，导致寿命增加。尽管大多数患者以前由于隔膜和肋间肌肉的无力而死于呼吸道衰竭，但已经观察到越来越老年患者死于呼吸道或心脏衰竭的患者。尽管如此，大多数DMD/BMD的治疗策略都集中在肢体肌肉上，多皮特证据表明骨骼肌救援会加剧心脏功能障碍。我们的实验室表明，与DMD的小鼠（MDX）和犬类模型相关的病毒（AAV）载体可以有效地靶向骨骼肌和心脏肌肉，并且系统性AAV的微型肌营养蛋白Cassettes的全身性递送可以停止渐进性营养不良的变化，并显着改善diaphragm and Cardiac cardiac和Cardiac cardiac corniac consmdxMiese。功能性救援虽然令人印象深刻，但并不完整，最近的研究提出了改善微肌营养蛋白功能和肌肉特异性表达的多种方法。测试和比较这些改良的微肺炎蛋白是由MDX小鼠表型的中度编译的，因此我们建议使用更严重影响的MDX4CV/DBA-2突变体，该突变体显示出广泛的心肺纤维化和更具渐进的病理学。这些盒式将在全身性AAV介导的基因转移到成年动物后，完成新的微肺炎cDNA和新的基因调节盒，以在呼吸道和心脏肌肉中的表达和功能优化。我们还将在旨在防止免疫介导的肌营养不良蛋白表达丧失的策略的背景下整合这些输送系统。这些包括一种新型的反疫苗方案，旨在诱导耐受性和瞬时免疫抑制。这些方法一起可以显着影响治疗DMD患者呼吸道和心脏肌肉的能力。这项工作对涉及心肺功能障碍的其他疾病的基因治疗也具有广泛的影响。