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

贝克肌营养不良症（BMD）是由肌营养不良蛋白基因突变引起的X连锁隐性遗传疾病。由于框内基因缺失或其他亚型等位基因，患者具有肌营养不良蛋白的部分功能丧失。迄今为止，BMD基因型/表型研究有限，并且没有多中心环境中的纵向自然史研究。 外显子跳跃的目的是产生BMD样的内部缺失的、符合读码框的肌营养不良蛋白，作为杜氏肌营养不良（DMD）患者的治疗干预。许多临床上轻度BMD患者已被描述，一些非常大的缺失，和一些谁只显示高血清肌酸激酶水平很少或没有相关的临床症状。然而，也有许多BMD患者具有杆结构域的框内缺失，其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表型对于设计和评估基于外显子跳跃的药物开发计划至关重要。 在这个项目中，我们提出了一个BMD参与者的自然史研究与特定的框内缺失，对应于外显子45，51或53的外显子跳跃产生的突变。这些反映了在本CORT中研究的三种反义寡核苷酸药物导致的DMD外显子跳跃的“靶向”缺失，因此将项目3与项目1和2联系起来。我们将使用临床研究中心的合作网络，国际神经肌肉研究合作组（CINRG）招募参与者。CINRG小组正在进行一项由联邦政府资助的348名DMD参与者的纵向历史研究，此外还有多项已完成和正在进行的临床试验。包括所有CINRG站点的当前普查为472名BMD患者。我们将描述BMD表型，并将特定的异常肌营养不良蛋白与临床结果的范围相关联。 作为BMD的第一个自然史研究，该项目在DMD的新兴分子治疗领域具有很高的影响力，并有助于进一步研究DMD的外显子跳跃治疗的翻译CORT重点。

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.