Becker muscular dystrophy: A natural history study to predict efficacy of exon sk

贝克尔肌营养不良症：预测外显子 sk 功效的自然史研究

• 批准号: 8102468
• 负责人: Paula R Clemens
• 金额: $ 48.54万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-09 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102468
• 关键词: Activities of Daily Living; Alleles; Antisense Oligonucleotides; Articular Range of Motion; Becker Muscular Dystrophy; Cardiac; Censuses; Childhood; Clinical; Clinical Data; Clinical Research; Clinical Trials; Clinical Trials Network; Core Biopsy; Creatine Kinase; Data; Disease; Duchenne muscular dystrophy; Dystrophin; Evaluation; Event; Exons; Fibroblasts; Funding; Future; Gene Deletion; Gene Mutation; Genes; Genotype; Goals; International; Link; Longitudinal Studies; Measures; Medical; Messenger RNA; Molecular; Muscle; Muscular Dystrophies; Mutation; Natural History; Neuromuscular Diseases; Outcome; Outcome Measure; Participant; Patients; Personal Satisfaction; Pharmaceutical Preparations; Phenotype; Proteins; Quality of life; Recording of previous events; Recruitment Activity; Research; Residual state; Serum; Severities; Site; Skin; Symptoms; Therapeutic; Therapeutic Intervention; Time; Translational Research; base; clinical phenotype; cognitive function; design; drug development; experience; insight; loss of function; neuromuscular; novel; programs; protein function; pulmonary function; retinal rods; tool

Becker muscular dystrophy (BMD) is an X-linked recessive disorder caused by mutations in tiie dystrophiin gene. Patients have partial loss-of-function of the dystrophin protein due to in-frame gene deletions, or other hypomorphic alleles. BMD genotype/phenotype studies have been limited to date, and there have been no longitudinal natural history studies in a multi-center setting. The intent ofexon skipping is to produce BMD-like internally deleted, in-frame dystrophin proteins as a therapeutic intervention for Duchenne muscular dystrophy (DMD) patients. Many clinically mild BMD patients have been described, some with very large deletions, and some who show only high serum creatine kinase levels with little or no associated clinical symptoms. However, there are also many BMD patients, with in-frame deletions of the rod domain, who have a severe muscle dystrophic phenotype, often as severe as the classic phenotype of DMD. A better understanding ofthe BMD phenotype is critical to the design and evaluation of drug development programs based on exon skipping. In this project, we propose a natural history study of BMD participants with specific in-frame deletions that correspond to the mutations generated by exon skipping of exons 45, 51 or 53. These reflect the 'target' deletions of DMD exon skipping resulting from the three antisense oligonucleotide drugs studied in this CORT, hence linking Project 3 with Projects 1 and 2. We will use a collaborative network of clinical research centers, the Cooperative International Neuromuscular Research Group (CINRG) to recruit participants. The CINRG group has an ongoing federally-funded longitudinal history study of 348 DMD participants in addition to multiple completed and ongoing clinical trials. The current census comprising all CINRG sites is 472 BMD patients. We will characterize the BMD phenotype, and correlate specific abnormal dystrophin proteins with the range of clinical outcomes. As the first natural history study for BMD, the proposed project has high impact in the field of emerging molecular therapeutics for DMD and contributes to the translational CORT focus of furthering research toward exon skipping therapy for DMD.

贝克肌营养不良症（BMD）是一种由肌营养不良蛋白基因突变引起的x连锁隐性疾病。由于框架内基因缺失或其他亚型等位基因，患者有肌营养不良蛋白的部分功能丧失。迄今为止，骨密度基因型/表型研究受到限制，也没有在多中心环境下进行的纵向自然历史研究。