Modulating Skeletal Muscle Regeneration by Delivery of Myeloid Lineage Cells

描述(申请人提供)：Duchenne肌营养不良症(DMD)是一种进行性、致命性、肌肉萎缩的疾病，每3500名男性新生儿中就有一人受到影响。虽然在通过基因治疗方法提高疾病的治疗水平方面已经取得了巨大的进展，但基因治疗的临床应用仍然是一个遥远的目标，需要改善病理的策略来降低疾病的严重性，直到治愈的方法被确立。DMD肌肉和MDX小鼠肌肉经历广泛的炎症，被认为加速了DMD的病理。然而，最近的发现表明，炎性浸润物是复杂的，一些免疫细胞促进肌肉再生。巨噬细胞调节营养不良肌肉损伤和修复的能力表明，对巨噬细胞功能的实验性操作可以提供一种影响DMD病理的策略。此外，巨噬细胞可以提供一种手段，将治疗分子快速定向选择性地输送到疾病最活跃的部位。这项研究的总体目标是使用DMD的MDX小鼠模型来检查免疫细胞是否可以作为载体来运送治疗分子，从而减少DMD的病理。我们的实验策略是通过清髓性照射抑制mdx小鼠的免疫隔膜，然后移植表达治疗性转基因或野生型的小鼠的骨髓细胞，然后检测对mdx肌肉病理和功能的影响。这项研究的结果将为向营养不良肌肉提供基因治疗的新机制提供新的见解，并为解决DMD这一重大健康问题的新治疗策略提供基础。

DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD) is a progressive, lethal, muscle wasting disease that affects 1 in 3500 newborn males. Although tremendous progress has been made in advancing cures for the disease through gene therapeutic approaches, clinical application of gene therapies remains a distant goal and strategies for ameliorating the pathology are needed to reduce disease severity until a cure is established. DMD muscle and mdx mouse muscle experience extensive inflammation that is believed to accelerate DMD pathology. However, recent discoveries have shown that the inflammatory infiltrate is complex and that some immune cells promote muscle regeneration. The ability of macrophages to modulate injury and repair of dystrophic muscles suggests that experimental manipulations of macrophage function could provide a strategy to influence DMD pathology. Furthermore, macrophages could provide a means for the targeted selective delivery of therapeutic molecules rapidly to sites where the disease is most active. The overall objective of this investigation is to use the mdx mouse model of DMD to examine whether immune cells can function as vectors to deliver therapeutic molecules that reduce the pathology of DMD. Our experimental strategy is to suppress the immune compartment of mdx mice by myeloablative irradiation, then transplant bone marrow cells obtained from mice expressing therapeutic transgenes or wild-type and then assay for effects on the mdx muscle pathology and function. The findings of this investigation will provide new insights into a novel mechanism for the delivery of gene therapy to dystrophic muscle and provide the foundation for new therapeutic strategies for addressing DMD, a significant health problem.