Micro-laminin Gene Therapy for MDC1A

MDC1A 的微层粘连蛋白基因治疗

基本信息

批准号：
10198254
负责人：
PAUL Taylor MARTIN
金额：
$ 20.33万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10198254
关键词：
Adult Affect Agrin Apoptosis Binding Birth Cessation of life Child Clinical Coupling Cytomegalovirus Dependovirus Disease Disease Outcome Duchenne muscular dystrophy Engineering Extracellular Matrix Genes Glycosaminoglycans Goals Gold Growth Health Heparin Binding Insulin-Like Growth Factor I Integrin alpha Chains Intravenous Laminin Life Mediating Membrane Mission Modeling Mus Muscle Muscle Cells Muscle Weakness Muscular Atrophy Muscular Dystrophies Mutate Patients Phenotype Process Protein Region Proteins Public Health Role Skeletal Muscle Symptoms Testing Therapeutic Time Treatment Efficacy United States National Institutes of Health Work adeno-associated viral vector alpha Dystroglycan base congenital muscular dystrophy curative treatments disability effective therapy experimental study gene replacement gene replacement therapy gene therapy loss of function mutation micro-dystrophin muscle form muscle strength muscular dystrophy mouse model overexpression premature prevent receptor therapeutic evaluation vector

项目摘要

SUMMARY/ABSTRACT Congenital Muscular Dystrophy 1A (MDC1A) is one of the most severe forms of muscular dystrophy, affecting children at birth and causing dramatic muscle weakness. There are currently no therapies for MDC1A that can ultimately impact disease outcomes. MDC1A arises from recessive loss of function mutations in the LAMA2 gene, which encodes laminin a2, the predominant a chain of laminin in the extracellular matrix (ECM) of skeletal muscle. The LAMA2 gene is too large to be packaged into Adeno Associated Virus (AAV) vectors, making gene replacement for MDC1A impossible with the current gold standard used for clinical gene therapy. We have engineered a micro-laminin gene therapy that can be used with AAV. The current studies will optimize the therapeutic strength of this micro-laminin gene therapy approach by engineering in an additional component to build new muscle strength. These therapies will then be tested in a model for MDC1A. In doing so, this work will develop a single AAV-mediated gene therapy treatment for patients with MDC1A that has the potential to stop and reverse the disease process.

摘要/摘要先天性肌肉营养不良1A（MDC1A）是最严重的肌肉形式之一营养不良，影响出生时儿童，并引起剧烈的肌肉无力。有目前尚无对MDC1A的疗法最终会影响疾病预后的疗法。 MDC1A出现从编码层粘连蛋白A2的LAMA2基因中功能突变的隐性丧失，骨骼肌的细胞外基质（ECM）中主要是层粘连蛋白链。这 LAMA2基因太大，无法包装到Adeno相关病毒（AAV）载体中，使使用用于临床基因的当前金标准的MDC1A的基因替换不可能治疗。我们已经设计了可与AAV一起使用的微氯胺酮基因疗法。这当前的研究将优化这种微叠明蛋白基因治疗的治疗强度通过在额外组成部分中进行工程技术来建立新的肌肉力量。这些然后，将在MDC1A的模型中对疗法进行测试。这样，这项工作将发展一个对MDC1A患者的AAV介导的基因治疗，有可能停止并扭转疾病过程。