Innovative Approaches to Treat Duchenne Muscular Dystrophy Using iPSC-Derived Muscle Progenitors

使用 iPSC 衍生的肌肉祖细胞治疗杜氏肌营养不良症的创新方法

基本信息

批准号：
10162502
负责人：
Muhammad Ashraf
金额：
$ 50万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10162502
关键词：
Apoptosis CXCR4 gene Cell Line Cell Transplantation Cells Cessation of life Clustered Regularly Interspaced Short Palindromic Repeats Coupled Data Defect Duchenne muscular dystrophy Dystrophin Engineering Engraftment Environment Gene Activation Gene Expression Genes Genetic Diseases Genetic Engineering Goals Growth Harvest Home Homing Impairment Injury Interleukin-10 Intravenous Ischemia Ischemic Preconditioning Limb structure Mediating Methodology Methods Mus Muscle Muscle Cells Muscle Weakness Muscle satellite cell Muscular Atrophy Myopathy Natural regeneration Pathology Patients Population Progenitor Cell Engraftment Proteins Protocols documentation Quality of life Reperfusion Therapy Signal Transduction Site Site-Directed Mutagenesis Skeletal Muscle Stearoyl-CoA Desaturase Stromal Cell-Derived Factor 1 System Testing Tissues Transplantation Viral Vector Wasting Syndrome base exosome experimental study genomic platform immune activation improved in vivo induced pluripotent stem cell inhibitor/antagonist innovation interest micro-dystrophin novel overexpression preconditioning progenitor public health relevance recruit regenerative repaired small molecule stem cell differentiation stem cell exosomes stem cells tumor tumorigenesis tumorigenic young man

项目摘要

DESCRIPTION (provided by applicant): Duchenne Muscular Dystrophy (DMD) is a lethal muscle wasting disease caused by the lack of dystrophin, which eventually leads to apoptosis of muscle cells and impaired muscle contractility. Induced pluripotent stem cells (iPSC) offer the potential to correct the DMD gene defect and create healthy cells for transplantation without causing immune activation. However, this requires engineering iPSCs to facilitate homing and engraftment into diseased muscle tissue without promoting tumorigenesis. Our long-term goal is to optimize the differentiation of iPSC into myogenic progenitor cells (MPC) that are directed to home into muscle tissue and engraft without undergoing unrestrained growth. Our central hypothesis is that precise MPC genetic engineering, coupled with targeted modification of the host muscle niche by preconditioning or exosome delivery, will boost homing and engraftment of donor iPSC-derived MPC via the SDF-CXCR4 axis to safely and effectively treat DMD. The rationale is to develop methodology to produce large quantities of functional MPC from patients with DMD that are tumor free and can effectively home to sites of muscle injury and facilitate repair. We plan to test our central hypothesis and accomplish the objectives of this application by pursuing the following three specific aims. In Aim 1, we will test the hypothesis that iPSC-derived progenitor cells are effective and safe for regeneration of dystrophic muscle. In Aim 2, we will test the hypothesis that activation of CXCR4 in iPSC-derived myogenic precursors from DMD mice using a CRISPR-on based genomic platform improves engraftment of donor cells in DMD mice. In Aim 3, we will test the hypothesis that optimizing the regenerative microenvironment in muscle by ischemic preconditioning or iPSC-exosome-mediated delivery of SDF-1α protein enhances the homing and/or survival of donor MPC to augment muscle repair. These experiments have the potential to demonstrate that transplantation of iPSC-derived progenitors, coupled with methods to optimize the host muscle microenvironment, will more effectively ameliorate dystrophic pathology and improve the quality of life for patients with DMD.

描述（由申请人提供）：杜氏肌营养不良症（DMD）是一种由肌营养不良蛋白缺乏引起的致命性肌肉消耗性疾病，最终导致肌肉细胞凋亡和肌肉收缩力受损。纠正 DMD 基因缺陷并创建用于移植的健康细胞，而不引起免疫激活。然而，这需要对 iPSC 进行改造，使其能够在不促进的情况下促进归巢并植入患病的肌肉组织中。我们的长期目标是优化 iPSC 向肌源性祖细胞 (MPC) 的分化，这些细胞可定向进入肌肉组织并移植，而无需进行无限制的生长。我们的中心假设是精确的 MPC 基因工程与靶向修饰相结合。通过预处理或外泌体递送来改变宿主肌肉生态位，将通过 SDF-CXCR4 轴促进供体 iPSC 衍生的 MPC 的归巢和植入，从而安全有效地治疗 DMD。我们计划通过追求以下三个具体目标来检验我们的中心假设并实现本应用的目标。在目标 1 中，我们将测试 iPSC 衍生的祖细胞对于营养不良性肌肉再生有效且安全的假设。在目标 2 中，我们将使用 DMD 小鼠测试 iPSC 衍生的肌源性前体细胞中 CXCR4 的激活这一假设。基于 CRISPR 的基因组平台可改善 DMD 小鼠中供体细胞的植入，我们将测试以下假设：通过缺血预处理或 iPSC 外泌体介导的 SDF-1α 蛋白递送来优化肌肉再生微环境可增强归巢。和/或供体 MPC 的存活以增强肌肉修复。这些实验有可能证明 iPSC 衍生祖细胞的移植，再加上优化宿主肌肉微环境的方法，将更有效地改善DMD患者的营养不良病理并提高生活质量。

项目成果

期刊论文数量（51）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Circular noncoding RNAs as potential therapies and circulating biomarkers for cardiovascular diseases.

环状非编码 RNA 作为心血管疾病的潜在疗法和循环生物标志物。

DOI：
发表时间：
2018-07
期刊：
影响因子：
8.2
作者：
Bayoumi, Ahmed S;Aonuma, Tatsuya;Teoh, Jian;Tang, Yao;Kim, Il
通讯作者：
Kim, Il

MiR322 mediates cardioprotection against ischemia/reperfusion injury via FBXW7/notch pathway.

MiR322 通过 FBXW7/Notch 通路介导针对缺血/再灌注损伤的心脏保护作用。

DOI：
10.1016/j.yjmcc.2019.05.020
发表时间：
2019-05-28
期刊：
Journal of molecular and cellular cardiology
影响因子：
5
作者：
Zixin Chen;Xuan Su;Yanxiang Shen;Yue Jin;Tong Luo;Il;N. Weintraub;Yaoliang Tang
通讯作者：
Yaoliang Tang

Aortic Aneurysm: In Defense of the Vascular Smooth Muscle Cell.

主动脉瘤：保护血管平滑肌细胞。

DOI：
10.1161/atvbaha.116.308356
发表时间：
2016-11
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
0
作者：
Kim HW;Weintraub NL
通讯作者：
Weintraub NL

Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way.

通过以 nSMase2 依赖性方式转移 microRNA-210 对细胞进行缺氧处理，可增强间充质干细胞外泌体的心肌修复功能。

DOI：
发表时间：
2018-12
期刊：
影响因子：
0
作者：
Zhu, Jinyun;Lu, Kai;Zhang, Ning;Zhao, Yun;Ma, Qunchao;Shen, Jian;Lin, Yinuo;Xiang, Pingping;Tang, Yaoliang;Hu, Xinyang;Chen, Jinghai;Zhu, Wei;Webster, Keith A;Wang, Jian'an;Yu, Hong
通讯作者：
Yu, Hong

Effective regeneration of dystrophic muscle using autologous iPSC-derived progenitors with CRISPR-Cas9 mediated precise correction.

使用自体 iPSC 衍生的祖细胞通过 CRISPR-Cas9 介导的精确校正有效再生营养不良的肌肉。