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

描述（由申请人提供）：Duchenne Muscular Dystrophy （DMD）是由肌营养不良蛋白（dystrophin）基因编码突变引起的，其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提高生活质量。最终治疗需要在所有受影响的肌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、基因疗法或两者的结合。我们希望移植一种特殊类型的肌肉修复细胞将帮助我们开发新的治疗方法来治疗这种疾病。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。为了有效地治疗DMD，需要保持自我更新能力的卫星细胞。因此，在本提案中，(1)我们将重点研究培养的卫星细胞如何维持其自我更新能力。此外，全身注射卫星细胞是一项必要的方案，将健康细胞提供给DMD患者所有受影响的肌肉组织。因此，(2)我们将尝试使用一种新的归巢受体表达来改进卫星细胞的系统递送方法。此外，我们需要使用不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提取的诱导多能干细胞（iPSCs）产生无限数量的卫星细胞。结合基因转导，这种协调一致的方法将帮助我们制造可以移植到患者体内的卫星细胞，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.