Micro-laminin Gene Therapy for MDC1A

总结/摘要 先天性肌营养不良1A（MDC 1A）是最严重的肌肉萎缩症之一。 营养不良，影响出生时的儿童，并造成严重的肌肉无力。有 目前还没有MDC 1A的治疗方法可以最终影响疾病结局。MDC 1A出现 由于编码层粘连蛋白a2的LAMA 2基因中的隐性功能缺失突变， 在骨骼肌的细胞外基质（ECM）中主要是层粘连蛋白链。的 LAMA 2基因太大而不能包装到腺相关病毒（AAV）载体中， MDC 1A的基因替代不可能与目前用于临床基因的金标准一起使用 疗法我们已经设计了一种可以与AAV一起使用的微层粘连蛋白基因疗法。的 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， 方法通过工程在一个额外的组成部分，以建立新的肌肉力量。这些 然后将在MDC 1A模型中测试治疗。在这样做的时候，这项工作将制定一个单一的 AAV介导的基因治疗有可能停止MDC 1A患者的治疗 并逆转疾病进程。

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.