Ablation of Non-Myogenic Progenitor Cells as a New Therapeutic Approach to Duchenne Muscular Dystrophy

消融非肌源性祖细胞作为杜氏肌营养不良症的新治疗方法

基本信息

批准号：
10013124
负责人：
Johnny Huard
金额：
$ 14.92万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-09 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10013124
关键词：
Ablation Acute Address Adipocytes Adipose tissue Adverse effects Affect Age Animal Model Animals Area Birth Cell Culture Techniques Cell Differentiation process Cell physiology Cells Chronic Chronic Disease Clinical Data Development Disease Disease Progression Drug Targeting Duchenne muscular dystrophy Dystrophin Fatty acid glycerol esters Fibroblasts Fibrosis Functional disorder Genetic Genetic Diseases Goals Hormonal Human Imatinib In Vitro Incidence Infiltration Inflammation Injury Intervention Investigational Therapies Knockout Mice Laboratories Lesion Measures Mediating Modeling Mus Muscle Muscle Cells Muscle Fibers Muscle Weakness Muscle function Muscular Dystrophies Mutation Myocardium Pathogenesis Pathogenicity Pathologic Pathology Patients Peptides Pharmaceutical Preparations Pharmacology Platelet-Derived Growth Factor Receptor Platelet-Derived Growth Factor alpha Receptor Population Prednisone Proliferating Protein Tyrosine Kinase Reporting Research Severities Site Skeletal Muscle Source Standardization Steroid therapy Steroids Stromal Cells Suicide Gene Therapy Techniques Technology Testing Therapeutic Thymidine Kinase TimeLine Tissues Utrophin Virus cell type experience gene correction gene therapy genetic approach inhibitor/antagonist lipid biosynthesis mesenchymal stromal cell mouse model muscle regeneration muscle strength novel novel strategies novel therapeutic intervention progenitor promoter recruit restoration sarcopenia satellite cell side effect skeletal muscle wasting standard of care stem cells suicide gene targeted treatment therapeutic target therapy development tissue regeneration transgenic suicide gene

项目摘要

Abstract Duchenne muscular dystrophy (DMD) is a deadly genetic disease characterized by a lack of dystrophin expression, resulting in progressive weakening and wasting of skeletal and cardiac muscles. Currently, there is no cure for DMD. The approved hormonal treatments have side effects and delay the disease progression only transiently. The emerging gene correction strategies, although effective in mouse models, are likely to be of limited immediate value to patients due to issues associated with virus-mediated gene therapy. Therefore, new approaches to suppress the disease progression are needed. Myogenic muscle progenitor cells (MPCs), also known as satellite cells, become dysfunctional (reduced proliferation and differentiation capacities) as disease progresses, coincidentally with reduced muscle regeneration, aggravating fatty infiltration, and fibrotic tissue accumulation in skeletal muscle. Mesenchymal stromal cells (MSCs) are non-myogenic progenitors of fibroblasts and adipocytes. We and others have reported that MSCs get activated during the disease progression in DMD and turn into fibroadipogenic progenitors (FAPs) that proliferate, induce MPC dysfunction and contribute to muscle pathology. Our preliminary data indicates that FAPs express markers of adipocyte progenitors, also known as adipose stromal cells (ASCs), the MSCs derived from fat tissue, suggesting ASCs as a source of FAPs. The goal of this application is to test whether DMD pathogenesis can be delayed via depletion of MSC-derived FAPs in the mouse model. In Aim 1, an inducible genetic ablation of proliferating MSC will be performed using a suicide transgene. In Aim 2, pharmacological ablation will be performed with a hunter-killer peptide targeting ASCs. We will test if DMD progression, measured as MPC dysfunction, fatty infiltration, fibrotic tissue accumulation, and the resulting loss of skeletal muscle function, can be suppressed by these experimental treatments. We predict that ablation of FAPs derived from MSCs/ASCs from the dystrophic milieu will delay MPC depletion and DMD progression. Information obtained from these studies will help develop new therapeutic approaches for treating muscular dystrophy.

抽象的杜氏肌营养不良症 (DMD) 是一种致命的遗传性疾病，其特征是缺乏肌营养不良蛋白表达，导致骨骼肌和心肌逐渐衰弱和消耗。目前，有 DMD 无法治愈。批准的激素治疗有副作用，只能延缓疾病进展短暂地。新兴的基因校正策略虽然在小鼠模型中有效，但其作用可能有限。由于与病毒介导的基因治疗相关的问题，对患者具有直接价值。因此，新的方法需要抑制疾病进展。肌源性肌肉祖细胞 (MPC)，也称为随着疾病的进展，卫星细胞变得功能失调（增殖和分化能力降低），与此同时，肌肉再生减少，脂肪浸润加剧，纤维化组织堆积骨骼肌。间充质基质细胞（MSC）是成纤维细胞和脂肪细胞的非肌源性祖细胞。我们和其他人报道说，间充质干细胞在 DMD 疾病进展过程中被激活，并转化为纤维脂肪祖细胞 (FAP) 增殖、诱导 MPC 功能障碍并导致肌肉病理学。我们的初步数据表明，FAP 表达脂肪细胞祖细胞（也称为脂肪细胞）的标记物基质细胞 (ASC)，即源自脂肪组织的 MSC，表明 ASC 是 FAP 的来源。此举的目标该应用的目的是测试 DMD 发病机制是否可以通过消除 MSC 衍生的 FAP 来延迟鼠标模型。在目标 1 中，将使用自杀手段对增殖的 MSC 进行诱导性基因消融转基因。在目标 2 中，将使用针对 ASC 的猎杀肽进行药物消融。我们将测试 DMD 是否进展，以 MPC 功能障碍、脂肪浸润、纤维化组织堆积和由此产生的骨骼肌功能丧失可以通过这些实验性治疗来抑制。我们预测消融源自营养不良环境的 MSC/ASC 的 FAP 将延迟 MPC 耗竭和 DMD 进展。从这些研究中获得的信息将有助于开发新的治疗方法肌肉萎缩症。