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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.

项目总结