Duchenne muscular dystrophy (DMD) is a progressive and lethal disease, caused by X-linked mutations of the dystrophin encoding gene. The lack of dystrophin leads to muscle weakness, degeneration, fibrosis, and progressive loss of skeletal, cardiac, and respiratory muscle function resulting in premature death due to the cardiac and respiratory failure. There is no cure for DMD and current therapies neither cure nor arrest disease progression. Thus, there is an urgent need to develop new approaches and safer therapies for DMD patients. We have previously reported functional improvements which correlated with increased dystrophin expression following transplantation of dystrophin expressing chimeric (DEC) cells of myoblast origin to the mdx mouse models of DMD. In this study, we demonstrated that systemic-intraosseous transplantation of DEC human cells derived from myoblasts of normal and DMD-affected donors, increased dystrophin expression in cardiac, respiratory, and skeletal muscles of the mdx/scid mouse model of DMD. DEC transplant correlated with preservation of ejection fraction and fractional shortening on echocardiography, improved respiratory function on plethysmography, and improved strength and function of the limb skeletal muscles. Enhanced function was associated with improved muscle histopathology, revealing reduced mdx pathology, fibrosis, decreased inflammation, and preserved muscle morphology and architecture. Our findings confirm that DECs generate a systemic protective effect in DMD-affected target organs. Therefore, DECs represents a novel therapeutic approach with the potential to preserve or enhance multiorgan function of the skeletal, cardiac, and respiratory muscles critical for the well-being of DMD patients.

中文翻译：

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人抗肌萎缩蛋白表达嵌合 (DEC) 细胞疗法可改善 Duchenne 肌营养不良症中的心脏、呼吸和骨骼肌功能

杜氏肌营养不良症 (DMD) 是一种进行性和致命的疾病，由肌营养不良蛋白编码基因的 X 连锁突变引起。肌营养不良蛋白的缺乏导致肌肉无力、退化、纤维化和骨骼、心脏和呼吸肌功能的进行性丧失，从而导致由于心力衰竭和呼吸衰竭而过早死亡。DMD 无法治愈，目前的疗法既不能治愈也不能阻止疾病进展。因此，迫切需要为 DMD 患者开发新的方法和更安全的疗法。我们之前曾报道过将表达肌营养不良蛋白的嵌合 (DEC) 成肌细胞来源的细胞移植到mdx后，与肌营养不良蛋白表达增加相关的功能改善DMD 的小鼠模型。在这项研究中，我们证明了来自正常和受 DMD 影响的供体的成肌细胞的 DEC 人细胞的全身骨内移植，增加了mdx/scid小鼠模型的心脏、呼吸和骨骼肌中肌营养不良蛋白的表达。DEC 移植与保留射血分数和超声心动图缩短分数、改善体积描记图的呼吸功能以及改善四肢骨骼肌的力量和功能相关。增强的功能与改善的肌肉组织病理学相关，显示mdx减少病理，纤维化，炎症减少，并保留肌肉形态和结构。我们的研究结果证实，DEC 在受 DMD 影响的靶器官中产生全身保护作用。因此，DECs 代表了一种新的治疗方法，有可能保留或增强对 DMD 患者的健康至关重要的骨骼、心脏和呼吸肌的多器官功能。