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.

Becker肌肉营养不良（BMD）是由die肌营养不良蛋白基因突变引起的X连锁隐性疾病。由于框内基因缺失或其他肌科等位基因，患者的肌营养不良蛋白蛋白的功能部分丧失。迄今为止，BMD基因型/表型研究已被限制，并且在多中心环境中没有纵向自然史研究。 跳过的目的是生产类似BMD的内部删除的，框内肌营养不良蛋白作为Duchenne肌肉营养不良（DMD）患者的治疗性干预措施。已经描述了许多临床温和的BMD患者，有些患者缺失很大，有些人仅显示高血清肌酸激酶水平，几乎没有或没有相关的临床症状。但是，还有许多BMD患者，具有杆状结构域的框架缺失，它们具有严重的肌肉营养不良表型，通常与DMD的经典表型一样严重。更好地了解BMD表型对于基于外显子跳过的药物开发计划的设计和评估至关重要。 在该项目中，我们提出了对BMD参与者的自然历史研究，其特定框内缺失与外显子跳过外显子45、51或53产生的突变相对应。这些突变反映了由三个反义寡核苷酸药物链接在CORT中，与Project ot link Projects进行了3个链接的项目，这些dmd外显子跳过了DMD外显子跳过的“目标”删除。中心，合作社国际神经肌肉研究小组（CINRG）招募参与者。 CINRG组除了多次完成和正在进行的临床试验外，还进行了348名DMD参与者的联邦资助纵向历史研究。当前包括所有CINRG站点的人口普查为472名BMD患者。我们将表征BMD表型，并将特异性异常肌营养不良蛋白与临床结局范围相关联。 作为BMD的首次自然史研究，该项目对DMD的新兴分子疗法领域具有很大影响，并有助于转化研究对外显子跳过DMD的焦点。