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)

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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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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

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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