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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center (P50)
Project #
5P50AR060836-05
Application #
8916547
Study Section
Special Emphasis Panel (ZAR1-KM)
Project Start
Project End
2017-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
5
Fiscal Year
2015
Total Cost
$379,985
Indirect Cost
$92,657
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
Jain, Harsh V; Boehler, Jessica F; Nagaraju, Kanneboyina et al. (2018) Synthesis, Characterization, and Function of an RNA-Based Transfection Reagent. Curr Protoc Nucleic Acid Chem 72:4.81.1-4.81.29
Yu, Qing; Morales, Melissa; Li, Ning et al. (2018) Skeletal, cardiac, and respiratory muscle function and histopathology in the P448Lneo- mouse model of FKRP-deficient muscular dystrophy. Skelet Muscle 8:13
Defour, Aurelia; Medikayala, Sushma; Van der Meulen, Jack H et al. (2017) Annexin A2 links poor myofiber repair with inflammation and adipogenic replacement of the injured muscle. Hum Mol Genet 26:1979-1991
Jain, H V; Boehler, J F; Verthelyi, D et al. (2017) An amphipathic trans-acting phosphorothioate RNA element delivers an uncharged phosphorodiamidate morpholino sequence in mdx mouse myotubes. RSC Adv 7:42519-42528
Vila, Maria C; Rayavarapu, Sree; Hogarth, Marshall W et al. (2017) Mitochondria mediate cell membrane repair and contribute to Duchenne muscular dystrophy. Cell Death Differ 24:330-342
Echigoya, Yusuke; Lim, Kenji Rowel Q; Trieu, Nhu et al. (2017) Quantitative Antisense Screening and Optimization for Exon 51 Skipping in Duchenne Muscular Dystrophy. Mol Ther 25:2561-2572
Benny Klimek, Margaret E; Sali, Arpana; Rayavarapu, Sree et al. (2016) Effect of the IL-1 Receptor Antagonist Kineret® on Disease Phenotype in mdx Mice. PLoS One 11:e0155944
Hathout, Yetrib; Seol, Haeri; Han, Meng Hsuan J et al. (2016) Clinical utility of serum biomarkers in Duchenne muscular dystrophy. Clin Proteomics 13:9
Coley, William D; Bogdanik, Laurent; Vila, Maria Candida et al. (2016) Effect of genetic background on the dystrophic phenotype in mdx mice. Hum Mol Genet 25:130-45
Hathout, Yetrib; Conklin, Laurie S; Seol, Haeri et al. (2016) Serum pharmacodynamic biomarkers for chronic corticosteroid treatment of children. Sci Rep 6:31727

Showing the most recent 10 out of 41 publications