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Understanding and Improving Therapies for the Muscular Dystrophies through Noninvasive Biomarkers

通过非侵入性生物标志物了解和改进肌营养不良症的治疗

基本信息

批准号：
10288585
负责人：
GLENN WALTER
金额：
$ 32.5万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-25 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10288585
关键词：
Age Animal Model Becker Muscular Dystrophy Bioenergetics Biological Markers Body mass index Calcium Chronic Clinical Data Clinical Management Clinical Research Clinical Trials Complement Data Development Disease Disease Marker Disease Progression Dose Duchenne muscular dystrophy Dystrophin Energy Metabolism Exposure to Fatty acid glycerol esters Future Genes Glucocorticoids Immune response Impairment Individual Infiltration Inflammation Inflammatory Limb-Girdle Muscular Dystrophies Magnetic Resonance Membrane Metabolic Metabolism Mitochondria Monitor Mus Muscle Muscular Atrophy Muscular Dystrophies Mutation Natural History Nature Obesity Participant Patients Pattern Pharmaceutical Preparations Pharmacology Phase I Clinical Trials Phenotype Population Proteins Regimen Research Personnel Respiratory Muscles Risk Factors Serum Skeletal Muscle Steroids Structure Therapeutic Effect Tissues Urine Work biomarker development biomarker identification boys cohort disease natural history gene therapy heart function improved in vivo insight metabolic profile metabolome metabolomics micro-dystrophin mitochondrial dysfunction muscle metabolism muscular structure neglect new therapeutic target novel novel marker patient population pre-clinical pre-clinical therapy repaired restoration small molecule synergism targeted biomarker therapeutic development therapeutic target therapy development treatment strategy

项目摘要

Project Summary/Abstract Project 3 serves as the translational project for this Center application, complementing preclinical therapeutic development in Projects 1 & 2. Building on our expertise in noninvasive magnetic resonance (MR) biomarker development, we will examine metabolic remodeling in patients with Duchenne muscular dystrophy (DMD) treated with emerging therapies and the most common form of limb girdle muscular dystrophy, LGMDR1 (also referred to as LGMD2A). Effective clinical management in both forms of muscular dystrophy will likely require multiple concomitant treatment strategies, which can have positive or negative metabolic consequences. Our central hypothesis is that disease progression in dystrophic muscle is associated with metabolic remodeling, which can be modulated by different pharmacologic strategies and exploited to provide novel biomarkers for therapeutic development. Obesity and an increase in metabolic risk factors have been recognized as hallmark features of DMD, exacerbated by chronic use of glucocorticoid steroids (GC). Micro-dystrophin (µDys) gene therapy has emerged as a promising treatment strategy, with significant restoration of dystrophin protein and favorable clinical data in early stage clinical trials. However, due to the truncated nature of the µDys protein, impaired nNOS localization and/or aberrant calcium handling are expected to persist post gene therapy (Focus of Project 1). In addition, immune response management requires concomitant chronic use of GC. To gain further insight into the effects of µDys gene therapy in individuals with DMD, Aim 1 will examine MR biomarkers of muscle metabolism, inflammation, and composition in DMD patients treated with AAV-µDys. The disease course will be characterized in multiple muscles and compared with the disease trajectory in untreated, age matched DMD (historical data) and Becker muscular dystrophy patients; the latter patients are expected to mirror the phenotypic profile post-gene therapy. In Aim 2, we will leverage extensive natural history data/biosamples and access to ongoing clinical studies to examine the effect of different GC dosing regimens (Synergy with Project 2) and chronic GC exposure on both muscle and whole-body metabolism in DMD. Finally, in Aim 3, we will extend our biomarker work to LGMDR1, an underserved patient population in therapeutic development. We will use a combination of MR biomarkers and metabolomics to characterize the natural history of disease progression and help identify therapeutic targets and novel biomarkers for future clinical trials.

项目总结/文摘