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ARRA Investments in Muscular Dystrophy-1

Public Health Burden
The muscular dystrophies are a group of more than 30 genetic diseases characterized by progressive weakness and degeneration of the skeletal muscles that control movement.  Some forms of muscular dystrophy (MD) are seen in infancy or childhood, while others may not appear until middle age or later.  The most common forms in children are Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy, which affect approximately 1 in every 3,500 to 5,000 boys in the United States.1 DMD patients are usually restricted to a wheelchair in their teens and die from cardiac dysfunction or respiratory complications in their late 20s or 30s

Basic Research into Muscle Biology
Muscle tissue normally exhibits a considerable capacity to regenerate after injury or disease.  The failure of regeneration contributes to the underlying cause and progression of muscular dystrophies as muscle tissue is slowly replaced by fibrous tissue and fat.  Better understanding of the basic mechanisms of muscle atrophy and regeneration, including the cell types and signaling pathways involved, may lead to novel treatment strategies for the muscular dystrophies and other muscle diseases.  Examples of efforts recently funded through ARRA grants include:
  • Identifying the molecular mechanisms that cause cells to develop into fully functional skeletal muscle fibers.2
  • Providing a dynamic learning environment for undergraduate students researching the processes involved in muscle development.3
Molecular Mechanisms of Muscle Diseases
All muscular dystrophies stem from genetic mutations.  These errors in the genetic code cause errors in the production of muscle proteins that are critical to proper muscle function to be misprogrammed or produced in insufficient quantities. The mechanisms, or pathways, that link a genetic mutation to disease phenotypes involve many different molecules that work together in a complex cascade of interactions.  Therefore, research into those genes and the associated molecular mechanisms connected to MD can lead to a better understanding of these diseases and potential approaches to their treatment or prevention.  A few examples of ARRA-funded grants that seek to explore these molecular pathways include:
  • Utilizing pluripotent cells derived from facioscapulohumeral muscular dystrophy (FSHD) patients to develop a greater understanding of FSHD on the molecular level, as well as potential genetic therapy options.4
  • Determining the role of MBNL, a protein that binds to RNA, in the disease state of myotonic dystrophy, as well as in normal cells.5
  • Investigating the molecular interactions between an enzyme called nNOS, and dystrophin, the protein whose deficiency is the root cause DMD.6
  • Examining the molecular mechanisms involved in misregulating CUGBP1 activity, a protein family identified in the development of myotonic dystrophy type 1 (DM1).7
  • Testing whether the modification of a particular enzyme can suppress muscle defects in multiple muscular dystrophy model systems.8
Potential Therapies
Although effective therapies for the muscular dystrophies are currently quite limited, understanding of the genetics and biochemistry of these diseases has led to several novel strategies. NIH ARRA funds in support of projects to develop and test these therapies include:
  • Identifying compounds that can improve the efficacy of a new therapeutic approach to DMD.9
  • Validating the potential of certain advanced imaging techniques to monitor disease progression, and the response to therapeutic interventions, in children with DMD.10
  • Understanding the structure of the protein that is defective in DMD, specifically, the area where most of the mutations responsible for DMD occur.11
  • Investigating a protein therapy that may prevent the breakdown of skeletal and heart muscles of DMD patients.12
  • Developing an improved mouse model for DM1 in order to accelerate progress in the testing of therapies.13
  • Testing the potential for treatment of FSHD by repressing the expression of certain genes involved in the disease.14
  • Characterizing the mechanism by which the overexpression of a protein called CT GalNAc transferase (CT) inhibits muscular dystrophy.15
  • Exploring pharmacological strategies in mouse models for the muscle fatigue and edema associated with muscular dystrophies and other neuromuscular diseases.16
  • Translating novel gene-based therapies for muscle disorders for the clinic.17

  1. Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, July 27, 2005
  2. 1R03AR057477-01 -- Pbx Homeodomain Proteins in Skeletal Muscle Differentiation -- Maves, Lisa (WA)
  3. 1R15AR055798-01A1 -- Utilization of a motility mutant to elucidate myotome formation in zebrafish -- Carver, Ethan A (TN)
  4. 1RC2AR058919-01 -- FSHD iPS cells: Modeling disease mechanisms, genetic correction and cell therapy -- Kyba, Michael (MN)
  5. 3R01AR053903-03S1 -- Molecular Mechanisms of Myotonic Dystrophy -- Berglund, John A (OR)
  6. 3R01AR049419-07S1 -- Dual AAV Vectors for Duchenne Muscular Dystrophy Therapy -- Duan, Dongsheng (MO)
  7. 2R01AR044387-11A2 -- Molecular Mechanisms of Myotonic Dystrophy -- Timchenko, Lubov T (TX)
  8. 1RC1AR058520-01 -- Generation of Wunen/LPP3-based therapy for muscular dystrophy -- Ruohola-Baker, Hannele (WA)
  9. 1RC1AR058333-01 -- Identification of Enhancers of Therapeutic Exon Skipping for DMD -- Miceli, M Carrie (CA)
  10. 1RC1AR058189-01 -- MR Monitoring of PTC124 Treatment in DMD -- Vandenborne, Krista H (FL)
  11. 3R01AR053970-03S1 -- Structure of the dystrophin rod in relation to exon boundaries and exon skipping -- Menhart, Nick (IL)
  12. 1R43AR056890-01A2 -- Intravenous Protein Therapy for the Treatment of Duchenne Muscular Dystrophy-- Hodges, Bradley L (MA)
  13. 3R01AR046806-09S1 -- Pathogenesis of Myopathy in Models of Myotonic Dystrophy -- Thornton, Charles A (NY)
  14. 3R01AR052027-03S1 -- Molecular Pathphysiology of FSHD muscular dystrophy via genome-wide approaches -- Chen, Yi-Wen (DC)
  15. 3R01AR049722-04S1 -- Glycosyltransferase Therapy for Myopathies -- Martin, Paul Taylor (OH)
  16. 3R01AR051199-05S1 -- Epsilon-sarcoglycan in LGMD Type 2D -- Campbell, Kevin P (IA)
  17. 3U54AR056953-02S1 -- Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center -- Samulski, Richard J (NC)

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