Mechanisms of mineralocorticoid receptor antagonism on inflammation in muscular dystrophy

盐皮质激素受体拮抗肌营养不良炎症的机制

基本信息

批准号：
10542800
负责人：
Jill A Rafael-Fortney
金额：
$ 44.72万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10542800
关键词：
Ablation Acute Address Adult Agonist Aldosterone Anti-Inflammatory Agents Antiinflammatory Effect Becker Muscular Dystrophy Binding Cardiac Cardiomyopathies Carrying Capacities Cells Chronic Clinical Clinical Data Clinical Trials Code Cytokine Receptor Gene Data Dependovirus Drug Combinations Drug usage Duchenne cardiomyopathy Duchenne muscular dystrophy Dystrophin Exercise FDA approved Fibrosis Gene Expression Gene Expression Profile Gene Transfer Genotype Glucocorticoids Human Immune Immune response Infiltration Inflammation Inflammatory Injury Lead Length Macrophage Measurement Membrane Methods Mineralocorticoid Receptor Modeling Molecular Mus Muscle Muscle Fibers Muscle satellite cell Muscular Atrophy Muscular Dystrophies Myelogenous Myeloid Cells Neuromuscular Diseases Outcome Pathogenesis Pathology Patients Population Prednisone Prevention Property Proteins Publishing Receptor Activation Receptor Inhibition Receptor Signaling Skeletal Muscle Sorting Spinal Fractures Spironolactone System Testing Transfection Transgenes Translating antagonist boys conditional knockout cytokine drug efficacy efficacy outcomes eplerenone fiber cell gene function gene therapy immune function improved mdx mouse micro-dystrophin middle age miniaturize mouse model muscle regeneration muscular dystrophy mouse model neuromuscular novel preclinical efficacy prednisolone prevent receptor repaired satellite cell side effect standard of care transgene expression

项目摘要

PROJECT SUMMARY Gene therapy for Duchenne Muscular Dystrophy (DMD) is currently being tested in clinical trials in young patients. However, limitations of the adeno-associated virus (AAV) delivery system, including its small carrying capacity and its low efficiency transfection of muscle stem cells, will remain a barrier to a cure. The miniaturized transgene being delivered that is based on a Becker muscular dystrophy dystrophin (micro- dystrophin) will still result in some skeletal muscle turnover with subsequent inflammation and cardiomyopathy. Additionally, injury resulting from normal muscle use will be repaired with muscle stem cells that will likely not express dystrophin. Both of these issues will result in at least low-level chronic inflammation, which will likely exacerbate muscle damage and ultimate loss of transgene expression, limiting efficacy. Prednisone, which has served as the standard of care for DMD, but has many severe side effects, continues to be given as an anti- inflammatory to prevent an immune response to the transgene. Published and preliminary data support the scientific premise that mineralocorticoid receptor (MR) antagonists, which have clinical benefit for DMD cardiomyopathy, stabilize muscle membranes, improve skeletal muscle force, and reduce fibrosis, are also anti-inflammatory and represent an ideal drug for combination with gene transfer. However, the anti- inflammatory properties of MR antagonists in muscular dystrophy have not been explored. Since prednisone directly competes with MR antagonist binding to its receptors, these studies are crucial for clinical use of MR antagonists as an adjunct therapy to replace prednisone. In this application, we will test whether prednisone and MR antagonists have the same or different effects on specific immune cell populations in dystrophic muscles, whether cytokine reductions by MR antagonists are dependent on MR signaling mechanisms in muscle fibers or myeloid cells, and whether MR antagonists limit accumulated damage after acute injury in dystrophic mice treated with micro-dystrophin gene therapy. We have developed methods to flow sort immune cell populations from single muscles from the mdx genotypic model of DMD that will allow the first identification of the immune cell populations suppressed by prednisone, despite decades of clinical use, and a direct comparison with MR antagonists. These methods will also allow for the unbiased identification of gene expression changes in inflammatory myeloid cells induced by MR antagonists and prednisone. These studies will inform optimal MR antagonist clinical use as a co-therapy to extend efficacy of emerging genetic therapies for DMD and potentially other forms of muscular dystrophies. The data generated will also identify novel potential anti-inflammatory treatment targets.

项目摘要 Duchenne肌营养不良症（DMD）的基因治疗目前正在年轻的临床试验中测试患者。但是，腺相关病毒（AAV）输送系统的局限性，包括其小载体容量及其肌肉干细胞的低效率转染将是治愈的障碍。这基于贝克肌营养不良的肌营养不良蛋白（微型 - 微型）的微型转基因肌营养不良蛋白）仍会导致一些骨骼肌更新，随后发炎和心肌病。此外，通过正常使用肌肉造成的伤害将用肌肉干细胞修复，这可能不会表达肌营养不良蛋白。这两个问题都至少会导致低级慢性炎症，这可能会导致加剧肌肉损害和转基因表达的最终丧失，限制了功效。泼尼松，有作为DMD的护理标准，但具有许多严重的副作用，继续以抗炎症以防止对转基因的免疫反应。发布和初步数据支持科学前提是矿物皮质激素受体（MR）拮抗剂，对DMD具有临床益处心肌病，稳定肌肉膜，改善骨骼肌肉力并减少纤维化，也是抗炎，代表与基因转移结合的理想药物。但是，抗尚未探索MR拮抗剂在肌营养不良症中的炎症特性。自泼尼松以来直接与MR拮抗剂与其受体结合的MR竞争，这些研究对于MR的临床使用至关重要拮抗剂作为替代泼尼松的辅助疗法。在此应用程序中，我们将测试是否泼尼松 MR拮抗剂对营养不良的特异性免疫细胞群具有相同或不同的影响肌肉，MR拮抗剂的细胞因子降低是否取决于MR信号机制肌肉纤维或髓样细胞，以及MR拮抗剂是否限制了急性损伤后的累积损伤用微型障碍蛋白基因治疗治疗的营养不良小鼠。我们已经开发了流动免疫的方法来自DMD的MDX基因型模型的单个肌肉的细胞群，该模型将允许首次识别尽管使用了数十年的临床使用，但仍被泼尼松抑制的免疫细胞群体和直接与MR拮抗剂的比较。这些方法还将允许对基因的公正识别 MR拮抗剂和泼尼松诱导的炎性髓样细胞的表达变化。这些研究将告知最佳MR拮抗剂临床用途作为辅助治疗，以扩大新兴基因疗法的功效对于DMD，以及潜在的其他形式的肌肉营养不良。生成的数据还将确定新颖潜在的抗炎治疗目标。