Modulating Skeletal Muscle Regeneration by Delivery of Myeloid Lineage Cells

描述（由申请人提供）：杜氏肌营养不良症（DMD）是一种进行性、致死性肌肉萎缩疾病，每3500名新生儿男性中就有1人患病。尽管通过基因治疗方法在推进疾病治疗方面取得了巨大进展，但基因治疗的临床应用仍然是一个遥远的目标，在治愈方法建立之前，需要改善病理的策略来降低疾病的严重程度。DMD肌肉和mdx小鼠肌肉经历广泛的炎症，这被认为是加速DMD病理。然而，最近的发现表明，炎症浸润是复杂的，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，实验操作巨噬细胞功能可能提供影响DMD病理的策略。此外，巨噬细胞可以提供一种靶向选择性地将治疗分子快速递送到疾病最活跃的部位的手段。本研究的总体目标是使用mdx小鼠DMD模型来检查免疫细胞是否可以作为载体传递减少DMD病理的治疗性分子。我们的实验策略是通过清髓照射抑制mdx小鼠的免疫室，然后移植表达治疗性转基因或野生型小鼠的骨髓细胞，然后检测对mdx肌肉病理和功能的影响。这项研究的发现将为基因治疗营养不良肌肉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.