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

• 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
• 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

 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）：杜氏和贝克肌营养不良症（DMD/BMD）是由肌营养不良蛋白基因突变引起的X连锁隐性遗传疾病。DMD是儿童最常见的致命遗传性疾病之一，但找到治愈方法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改进治疗方法正在导致寿命的延长。虽然大多数患者之前死于由于膈肌和肋间肌无力导致的呼吸衰竭，但已观察到死于呼吸衰竭或心力衰竭的患者人群年龄越来越大。尽管如此，大多数DMD/BMD的治疗策略都集中在肢体肌肉上，尽管有证据表明骨骼肌救援会加剧心功能障碍。我们的实验室已经表明，腺相关病毒（AAV）载体可以有效地靶向DMD的小鼠（mdx）和犬模型中的骨骼肌和心肌，并且微肌营养不良蛋白盒的系统性AAV递送可以停止进行性营养不良变化并显著改善mdx小鼠中的隔膜和心脏功能。功能拯救，虽然令人印象深刻，是不完整的，最近的研究表明，多种方法来提高功能和肌肉特异性表达的微肌营养不良蛋白。由于mdx小鼠表型的温和性，测试和比较这些修饰的微肌营养不良蛋白是复杂的，因此我们建议使用受影响更严重的mdx 4cv/Dba-2突变体，其显示广泛的心肺纤维化和更渐进的病理学。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，其在全身性AAV介导的基因转移至成年动物后在呼吸肌和心肌中优化表达和功能。我们还将整合这些交付系统的背景下，旨在防止免疫介导的肌营养不良蛋白表达的损失的战略。这些包括一种新的反向疫苗方案，旨在诱导耐受性和短暂的免疫抑制。这些方法可以显著影响治疗DMD患者呼吸和心肌的能力。这项工作对其他涉及心肺功能障碍的疾病的基因治疗也有广泛的意义。