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).

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center (P50)
Project #
5P50AR060836-03
Application #
8544772
Study Section
Special Emphasis Panel (ZAR1-KM (M1))
Program Officer
Nuckolls, Glen H
Project Start
2011-09-09
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$1,469,599
Indirect Cost
$388,540
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
Sreetama, S C; Takano, T; Nedergaard, M et al. (2016) Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis. Cell Death Differ 23:596-607
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
Boca, Simina M; Nishida, Maki; Harris, Michael et al. (2016) Discovery of Metabolic Biomarkers for Duchenne Muscular Dystrophy within a Natural History Study. PLoS One 11:e0153461
Hathout, Yetrib; Conklin, Laurie S; Seol, Haeri et al. (2016) Serum pharmacodynamic biomarkers for chronic corticosteroid treatment of children. Sci Rep 6:31727
Loell, Ingela; Raouf, Joan; Chen, Yi-Wen et al. (2016) Effects on muscle tissue remodeling and lipid metabolism in muscle tissue from adult patients with polymyositis or dermatomyositis treated with immunosuppressive agents. Arthritis Res Ther 18:136
Dillingham, Blythe C; Benny Klimek, Margaret E; Gernapudi, Ramkishore et al. (2015) Inhibition of inflammation with celastrol fails to improve muscle function in dysferlin-deficient A/J mice. J Neurol Sci 356:157-62
Hathout, Yetrib; Brody, Edward; Clemens, Paula R et al. (2015) Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy. Proc Natl Acad Sci U S A 112:7153-8
Freishtat, R J; Nino, G; Tsegaye, Y et al. (2015) Pharmacologically-induced mitotic synchrony in airway epithelial cells as a mechanism of action of anti-inflammatory drugs. Respir Res 16:132
Echigoya, Yusuke; Aoki, Yoshitsugu; Miskew, Bailey et al. (2015) Long-term efficacy of systemic multiexon skipping targeting dystrophin exons 45-55 with a cocktail of vivo-morpholinos in mdx52 mice. Mol Ther Nucleic Acids 4:e225

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