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

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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.