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Muscle-specific AAV Vectors for DMD Gene Therapy

用于 DMD 基因治疗的肌肉特异性 AAV 载体

基本信息

批准号：
7255164
负责人：
RICHARD J SAMULSKI
金额：
$ 18.83万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-13 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7255164
关键词：
Actins Affect Animal Model Animals Appendix Binding Biological Assay Capsid Cell Adhesion Cell membrane Cells Cessation of life Clinical Trials Codon Nucleotides Creatine Kinase Cytoskeleton DNA Sequence DNA Shuffling Dependovirus Development Duchenne muscular dystrophy Dystrophin Dystrophin-Associated Proteins Engineering Exercise Tolerance Extracellular Matrix Future Gene Delivery Genes Genetic Human Image Insertional Mutagenesis Integrin Binding Integrins Intramuscular Intravenous Invasive Laminin Libraries Life Ligands Limb structure Link Luciferases Monitor Muscle Muscle Cells Muscle Fibers Muscle Proteins Muscular Dystrophies Myocardium Myopathy Numbers Patients Peptides Phase Process Protein Isoforms Protein Overexpression Proteins RNA analysis Reagent Recovery Research Design Research Proposals Respiratory Diaphragm Route Sarcoglycans Seminal Serotyping Serum Site Skeletal Muscle Skeletal system Surface Tail Techniques Testing Therapeutic Transgenes Translational Research Validation Veins Virus adeno-associated viral vector adhesion receptor base combinatorial design directed evolution exhaustion gene therapy intraperitoneal male mdx mouse migration mini-dystrophin miniaturize mouse model mutant novel protein expression receptor reconstitution scaffold therapeutic transgene vector

项目摘要

DESCRIPTION (provided by applicant): Duchenne Muscular Dystrophy (DMD), which affects one in 3500 males, causes progressive myopathy of skeletal and cardiac muscles and premature death due to a lack of expression of the protein dystrophin in muscle tissues. Genetic replacement of defective protein with a functional, miniaturized form of dystrophin represents a promising approach for the treatment of DMD. The aforementioned minidystrophin transgene is currently being evaluated in human clinical trials using AAV vectors as agents for intramuscular delivery. The current exploratory/developmental research proposal is focused on the design and development of novel AAV vectors with enhanced gene delivery efficiency in dystrophic skeletal muscle using the mdx mouse model. Rationale for the exploratory phase of the translational research hinges on the overexpression of integrin a7¿1 in dystrophic muscle and our seminal finding that modulation of a putative integrin-binding domain on AAV2 capsids affects their ability to transduce normal skeletal muscle. We have formulated specific design strategies based on the aforementioned finding that include: (a) rational engineering of the integrin-binding domain to develop integrin a7¿1-targeted AAV vectors that transduce dystrophic muscle with high efficiency and (b) combinatorial engineering of AAV vectors that efficiently transduce dystrophic muscle in mdx mice. During the developmental phase, novel AAV vectors selected through this process will be utilized to deliver an enhanced minidystrophin transgene for therapeutic application in the mdx mouse model. Research design involves rational insertion peptide ligands to generate integrin a7¿1-targeted AAV vectors, directed evolution of dystrophic muscle-specific vectors obtained from an AAV mutant library administered into mdx mice through different routes of administration, and therapeutic application of an enhanced mini-dystrophin transgene construct in the mdx mouse model. The novel reagents developed and optimized in this proposal will be advanced for further therapeutic testing in larger animal models of muscular dystrophy and eventually in human muscular dystrophy clinical trials in the near future. Duchenne Muscular Dystrophy (DMD), which affects one in 3500 males, causes progressive myopathy of skeletal and cardiac muscles and premature death due to a lack of expression of the protein dystrophin in muscle tissues. The current exploratory/developmental research proposal is focused on the design and development of novel AAV vectors with enhanced gene delivery efficiency in dystrophic skeletal muscle using the mdx mouse model. The novel reagents developed and optimized in this proposal will be advanced for further therapeutic testing in larger animal models of muscular dystrophy and eventually in human clinical trials in the near future.

描述（由申请人提供）：杜氏肌营养不良症（DMD），其影响3500名男性中的一名，由于肌肉组织中肌营养不良蛋白的表达缺乏，导致骨骼肌和心肌的进行性肌病和过早死亡。用功能性的、小型化形式的肌营养不良蛋白基因替代缺陷蛋白代表了治疗DMD的有希望的方法。目前正在使用AAV载体作为肌内递送试剂的人类临床试验中评估上述微肌萎缩蛋白转基因。目前的探索性/开发性研究提案集中于使用mdx小鼠模型设计和开发在营养不良骨骼肌中具有增强的基因递送效率的新型AAV载体。翻译研究探索阶段的基本原理取决于营养不良肌肉中整合素α 7 β 1的过表达以及我们的开创性发现，即AAV 2衣壳上推定的整合素结合结构域的调节影响其激活正常骨骼肌的能力。我们已经基于上述发现制定了具体的设计策略，包括：（a）整合素结合结构域的合理工程化以开发高效抑制营养不良肌肉的整合素α 7 β 1靶向AAV载体和（B）有效抑制mdx小鼠中营养不良肌肉的AAV载体的组合工程化。在发育阶段，通过该过程选择的新型AAV载体将用于递送增强的小肌萎缩蛋白转基因，用于mdx小鼠模型中的治疗应用。研究设计涉及合理的插入肽配体以产生整合素α 7 β 1靶向的AAV载体，从通过不同给药途径给予mdx小鼠的AAV突变体文库获得的营养不良性肌肉特异性载体的定向进化，以及增强的微小肌营养不良蛋白转基因构建体在mdx小鼠模型中的治疗应用。在该提案中开发和优化的新型试剂将在不久的将来用于更大的肌营养不良症动物模型的进一步治疗测试，并最终用于人类肌营养不良症临床试验。杜氏肌营养不良症（DMD）影响3500名男性中的一名，其导致骨骼肌和心肌的进行性肌病以及由于肌肉组织中缺乏蛋白质肌营养不良蛋白的表达而导致的过早死亡。目前的探索性/开发性研究提案集中于使用mdx小鼠模型设计和开发在营养不良骨骼肌中具有增强的基因递送效率的新型AAV载体。在该提案中开发和优化的新型试剂将在不久的将来用于更大的肌营养不良症动物模型的进一步治疗测试，并最终用于人类临床试验。