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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：
10393047
负责人：
PAUL Taylor MARTIN
金额：
$ 16.77万
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10393047
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 Merosin-Deficient Congenital Muscular Dystrophy 1A 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/摘要先天性肌营养不良症 1A (MDC1A) 是最严重的肌肉萎缩症之一营养不良，影响出生时的儿童并导致严重的肌肉无力。有目前尚无能够最终影响疾病结果的 MDC1A 疗法。 MDC1A 出现编码层粘连蛋白 a2 的 LAMA2 基因隐性功能丧失突变骨骼肌细胞外基质（ECM）中主要有层粘连蛋白链。这 LAMA2基因太大，无法包装到腺相关病毒（AAV）载体中，使得目前用于临床基因的金标准不可能实现 MDC1A 的基因替代治疗。我们设计了一种可与 AAV 一起使用的微层粘连蛋白基因疗法。这目前的研究将优化这种微层粘连蛋白基因疗法的治疗强度通过设计附加组件来增强新的肌肉力量的方法。这些然后将在 MDC1A 模型中测试疗法。在此过程中，这项工作将开发一个单一的 AAV 介导的基因疗法对 MDC1A 患者的治疗有可能停止并逆转疾病进程。