The identification of the Duchenne muscular dystrophy gene and protein in the late 1980's led to high hopes of rapid translation to rational therapeutics. Early reports of delivering new functional genes to mouse model muscle via gene therapy and stem cell therapy fueled this hope. However, these same studies illuminated the very high hurdles facing human applications. Insufficient therapeutic material (cells, viral vectors), challenges in systemic delivery, and immunological hurdles all remain barriers to demonstration of efficacy of exogenous gene delivery. An alternative approach Is to repair the patient's own gene, and two innovative small molecule approaches have emerged as front-line experimental therapeutics: stop codon read through, and exon skipping. Both approaches are In human clinical trials, and aim to coax dystrophin protein production from mutant genes. In the clinically severe dog model of DMD, the exon-skipping approach is the first therapeutic method that showed improvement of multiple functional outcomes. The proposed CORT is focusing on exon-skipping, the approach that holds promise for the majority of DMD patients. Exon skipping as a drug development program Is highly complex. Patients have different mutations, and drugs must be customized to groups of patients sharing overlapping deletions. Given the high cost of drug development, there is an emerging consensus that exon skipping should achieve drug approval 'as a class'. Three exon-specific drugs should be systematically studied, showing safety and efficacy. The procedures and rules optimized for these three drugs can then be generalized to other, less commonly applicable exon- specific drugs, with reduced regulatory hurdles. The goal of this CORT is to systematically study the three most commonly applicable exon-specific drugs (exons 45,51.53). Project 1 will determine the splicing fidelity and protein function corresponding to the In-frame transcripts generated by the drugs. Project 2 will optimize sequence selection for each exon using multiple experimental systems, and test optimized drugs in a 1 yr pre-clinical efficacy study. Project 3 will carry out the first natural history study of the targeted in-frame deletions (Becker muscular dystrophy);this will permit some prediction of clinical efficacy from production of the relevant semi-functional dystrophin proteins. These three Projects draw upon two research cores: Core B (In vitro and In vivo functional assays), and Core C (Molecular diagnostics and cell banking).

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Specialized Center (P50)
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Special Emphasis Panel (ZAR1)
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Boyce, Amanda T
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Children's Research Institute
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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

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