Genetically Engineered Muscle Stem Cell Transplantation for Muscular Dystrophy...

描述（由申请人提供）：杜氏肌营养不良症（DMD）是由编码肌营养不良蛋白的基因突变引起的，肌营养不良蛋白的功能是维持肌纤维结构和功能，防止其因肌肉收缩而受损。目前，对DMD患者没有明确的治疗方法。目前的治疗重点是延长生存期和改善生活质量。持续治疗将需要在所有受影响的肌肉群中恢复功能性肌营养不良蛋白。可能的方法包括细胞疗法、基因疗法或两者的组合。我们希望移植一种特殊类型的肌肉修复细胞将有助于我们开发治疗这种疾病的新方法。从健康供体或患者中分离的肌肉干细胞，称为卫星细胞，应该能够提供肌营养不良蛋白并修复DMD患者的肌肉损伤。为了有效治疗DMD，维持自我更新能力的卫星细胞是必需的。因此，在本提案中，（1）我们将重点研究培养的卫星细胞如何保持自我更新能力。此外，全身注射卫星细胞是一种重要的方案，将为DMD患者的所有受影响的肌肉组织提供健康的细胞。因此，（2）我们将尝试使用新的归巢受体表达来改进卫星细胞的全身递送方法。此外，我们需要使用不会被患者免疫系统排斥的细胞。(3)我们能够从患者的成肌细胞中产生无限数量的诱导多能干细胞（iPSC）。与基因转导相结合，这种协同的方法将帮助我们制造卫星细胞，这些细胞可以移植到患者体内，从而彻底治愈DMD。

DESCRIPTION (provided by applicant): Duchenne Muscular Dystrophy (DMD) is caused by mutations in the gene coding for dystrophin, which functions to maintain muscle fiber structure and function, preventing it from being damaged by muscle contraction. Presently, there is no definitive treatment for DMD patients. Current therapies focus on prolonging survival and improving quality of life. Definitive treatment will require that functional dystrophin protein is restored in all affected muscle groups. Possible approaches include cell therapy, gene therapy or a combination of the two. We hope that transplantation of a particular type of muscle repair cell will help us to develop new therapeutic approaches to this disease. Muscle stem cells, termed satellite cells, isolated from healthy donors or patients should be able to provide dystrophin and repair muscle damage in DMD patients. For efficient therapy of DMD, satellite cells which maintain the self-renewing ability are necessary. Therefore, in this proposal, (1) we will focus on the study of how cultured satellite cells maintain their self-renewal capacity. In addition, systemic injection of satellite cells is an essential protocol that will provide healthy ells into all affected muscle tissues in DMD patients. Thus, (2) we will attempt to improve systemic delivery methods for satellite cells using a novel homing receptor expression. Furthermore, we need to use cells that are not rejected by a patient's immune system. (3) We are able to generate an unlimited number of satellite cells from induced pluripotent stem cells (iPSCs) derived from the patient's myoblasts. In combination with gene transduction, this concerted approach will help us to make satellite cells that can be transplanted into patients for a definitie cure of DMD.