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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 - PowerPoint PPT Presentation
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Updates in Research for Becker Muscular Dystrophy
Paula R. Clemens, MD
BMDDMD
Effect of type of mutation on dystrophin quality and quantity
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
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
Muscle Fiber Repair
Satellite Cell Activation Inflammation
Release of Cytokines( e.g. TGF-b)
Fibrosis(Formation of Scar Tissue)
_
+
Effect of NF-B on muscle
Nucleus
NF-B MuRF1Fibrogenic chemokine induction
Protein degradation
Recruitment of macrophages and other
inflammatory cells
Muscle degeneration and atrophy
NEMO-Binding Domain (NBD) Peptide Therapy in a Mouse Model of Muscular Dystrophy
8K: KKKKKKKK
TALDWSWLQTE
Transduction Domain
NBD (IKK Blocking) Peptide
Bind to IKK to prevent formation of IKK complex and thus prevent activation of NF-B
Mechanism of action:
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Tibialis anterior muscle – 8K-L-NBD treatment
Saline
8K-NBD
Hematoxylin & Eosin Necrosis Regeneration
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
Neurology, January 11, 2005
Prednisolone
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Deflazacort
CINRG Duchenne Natural History StudyGeographic Distribution of Participants (N=340)
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
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, Arpana Sali, Brittany K. Miller, Aditi Phadke, Luana Scheffer, 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, Kanneboyina Nagaraju
EMBO Mol Med (2013) 5, 1569–1585
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
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
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
The Cooperative International Neuromuscular Research Group
(CINRG)
www.cinrgresearch.org
• 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
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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