Micro-laminin Gene Therapy for MDC1A

摘要/摘要 先天性肌营养不良症(MDC1A)是最严重的肌肉疾病之一 营养不良，在孩子出生时就会受到影响，并导致剧烈的肌肉无力。确实有 目前还没有治疗MDC1A的方法可以最终影响疾病的结果。MDC1a出现 由于编码层粘连蛋白a2的LAMA2基因的隐性功能突变， 在骨骼肌细胞外基质(ECM)中占主导地位的层粘连蛋白链。这个 LAMA2基因太大，无法包装入腺相关病毒载体，使 用目前临床基因的黄金标准不可能进行MDC1A的基因替换 心理治疗。我们已经设计出一种微型层粘连蛋白基因疗法，可以用于AAV。这个 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 通过在工程中添加额外的组件来建立新的肌肉力量的方法。这些 然后，治疗方法将在MDC1A的模型中进行测试。在这样做的过程中，这项工作将开发一个单一的 AAV介导的MDC1a患者有可能停止的基因治疗 并逆转疾病的进程。

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.