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Updates in Research for Becker Muscular Dystrophy

Updates in Research for Becker Muscular Dystrophy. Paula R. Clemens, MD. Effect of type of mutation on dystrophin quality and quantity. DMD. BMD. Issues that specifically impact research planning for BMD therapy. Single gene disorder that is known

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Updates in Research for Becker Muscular Dystrophy

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  1. Updates in Research for Becker Muscular Dystrophy Paula R. Clemens, MD

  2. Effect of type of mutation on dystrophin quality and quantity DMD BMD

  3. Issues that specifically impact research planning for BMD therapy • Single gene disorder that is known • The clinical presentation is highly heterogeneous • The disease is very rare—affected individuals are not clustered • Effects of the genetic defect are complex, triggering pathological pathways in skeletal and cardiac muscle that are inflammatory

  4. + Inflammation Satellite Cell Activation _ Release of Cytokines ( e.g. TGF-b) Muscle Fiber Repair Fibrosis (Formation of Scar Tissue) Progression of Dystrophic Myopathy in BMD Defective Dystrophin Gene Decreased Quantity and/or Quality of Dystrophin Protein Damage to Individual Muscle Fibers Death of Groups of Muscle Fibers

  5. Effect of NF-B on muscle Fibrogenic chemokine induction NF-B MuRF1 Nucleus Recruitment of macrophages and other inflammatory cells Protein degradation Muscle degeneration and atrophy

  6. n=5 * n=4 8K-NBD peptide Saline NEMO-Binding Domain (NBD) Peptide Therapy in a Mouse Model of Muscular Dystrophy Transduction Domain 8K: KKKKKKKK • NBD (IKK Blocking) Peptide • TALDWSWLQTE C Mechanism of action: 0.2000 Bind to IKK to prevent formation of IKK complex and thus prevent activation of NF-B 0.1500 Average Band Density 0.1000 0.0500 0.0000

  7. Tibialis anterior muscle – 8K-L-NBD treatment Hematoxylin & Eosin Necrosis Regeneration Saline 8K-NBD • Reay DP, Yang M, Rehman KK, O’Day TL, Guttridge DC, Robbins PD, Clemens PR. Systemic delivery of NEMO binding domain/IKK inhibitory peptide to young mdx mice improves dystrophic skeletal muscle histopathology. Neurobiol Dis 2011. 43(3): 598-608. PMCID: PMC3145633

  8. CH2OOCCH3 CH2OH CH3 CO CO CH3 CH3 N HO HO O CH3 CH3 O O Neurology, January 11, 2005 Prednisolone Deflazacort

  9. CINRG Duchenne Natural History StudyGeographic Distribution of Participants (N=340)

  10. Glucocorticoid (GC) treatment confers benefits across all ages and milestones for DMDCINRG Duchenne Natural History Study • Delay loss of ambulation by up to 3 years • Alter natural history of scoliosis development • Delay loss of upper extremity function—able to self-feed longer • However, there are many side effects to GC (behavioral, growth inhibition, delayed puberty) and their use has not been studied in BMD. • Henricson E et al and CINRG Investigators. The CINRG Duchenne natural history study: Glucocorticoid treatment preserves clinically-meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures. Muscle Nerve 2013 Jul;48 (1):55-67. PMID:23649481

  11. VBP15, a novel anti‐inflammatory and membrane‐stabilizer, improves muscular dystrophy without side effects Christopher R. Heier, Jesse M. Damsker, Qing Yu1, Blythe C. Dillingham, Tony Huynh, Jack H. Van der Meulen, ArpanaSali, Brittany K. Miller, AditiPhadke, LuanaScheffer, James Quinn, Kathleen Tatem, Sarah Jordan, Sherry Dadgar, Olga C. Rodriguez, Chris Albanese, Michael Calhoun, Heather Gordish-Dressman, Jyoti K. Jaiswal, Edward M. Connor, John M. McCall, Eric P. Hoffman, Erica K. M. Reeves, KanneboyinaNagaraju EMBO Mol Med (2013) 5, 1569–1585

  12. EMBO Molecular MedicineVolume 5, Issue 10, pages 1569-1585, 9 SEP 2013 DOI: 10.1002/emmm.201302621http://onlinelibrary.wiley.com/doi/10.1002/emmm.201302621/full#emmm201302621-fig-0004

  13. VBP15, a novel anti‐inflammatory and membrane‐stabilizer, improves muscular dystrophy without side effects EMBO Molecular MedicineVolume 5, Issue 10, pages 1569-1585, 9 SEP 2013 DOI: 10.1002/emmm.201302621http://onlinelibrary.wiley.com/doi/10.1002/emmm.201302621/full#emmm201302621-fig-0007

  14. Conclusions • Inflammatory changes in dystrophin-deficient muscle are mediated by signaling pathways, such as NF-B • Inhibition of the NF-B pathway has potential as a therapeutic approach • Multiple means of inhibiting NF-B show promise • Novel glucocorticoid development has potential to limit side effects of treatment • Inhibition of microRNAs to maximize truncated dystrophin protein levels, provides another therapeutic avenue

  15. The Cooperative International Neuromuscular Research Group (CINRG) • Clinical research network focused on muscular dystrophy research initiated in 2000 • More than 25 clinical study sites worldwide • Project management, data management and statistics provided by the CINRG Coordinating Center • Data Safety Monitoring Board; Scientific Advisory Board; Subcommittees on Outcomes, Therapeutics and Publications • Partnerships with foundations, NIH and pharmaceutical industry www.cinrgresearch.org

  16. CINRG Studies for BMD • CoQ10 and Lisinopril for Treatment of Muscular Dystrophies • To determine if CoQ10, lisinopril or both are effective in delaying the onset of heart involvement in individuals with muscular dystrophy • Becker Muscular Dystrophy: A Natural History Study • To better characterize the myriad effects of BMD on affected individuals, which will help to develop outcome measures for future clinical trials

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