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ARRA Investments in Muscular Dystrophy-2

Public Health Burden
The muscular dystrophies (MDs) are a group of diseases that cause weakness and progressive degeneration of skeletal muscles, resulting in mild to moderate disability for some forms of MD and death in others. The most common form is Duchenne MD. Between 400 and 600 boys in the United States are born with Duchenne and Becker (a milder form of the condition) MD each year. Myotonic dystrophy, the most common adult form, affects about 1 in 8,000 people worldwide. Other forms of MD include limb-girdle (LGMD), facioscapulohumeral, oculopharyngeal, and Emery-Dreifuss.

Understanding Molecular Mechanisms
Since the 1980’s, researchers have learned much about how mutations in the dystrophin gene lead to muscle degeneration in Duchenne and Becker MD. For other forms of MD, mechanistic knowledge is less advanced and ARRA-funded projects are focused on understanding these mechanisms. Uncovering the molecular mechanisms of these disorders is critical to identify potential therapeutic targets.
  • A Challenge Grant will explore why mutations in the gene PABPN1 cause oculopharyngeal MD and the accompanying weakness and atrophy restricted to head and neck muscles.1
  • A study will investigate the role of certain proteins – the ferlins – in LGMD type 2B, including how these proteins contribute to muscle growth and repair at the muscle membrane. In addition to gaining insight into LGMD type 2B, the results will help with developing general strategies to promote muscle growth and repair.2
  • A project will determine how defects in the structure of the cell nucleus (the cell’s “control center”) cause abnormal muscle function in Emery-Dreifuss MD.3
  • ARRA funding will be used to expand an ongoing project to understand the genetic and molecular mechanisms of facioscapulohumeral MD by characterizing in more detail the abnormal repeated genetic sequence found in this disorder and examining how this genetic abnormality may affect nearby genes.4
Preclinical Therapy Development
While there is currently no treatment that can stop or reverse the progression of any form of muscular dystrophy, the development of therapies has begun to show significant progress in recent years. ARRA funded research is furthering preclinical development of a number of therapeutic strategies.
  • A “GO” grant will identify small molecules that alter the protein dystroglycan, a support protein in muscle cells that gets chemically modified in order to function. Disruption of this modification process results in several forms of MD, known as the dystroglycanopathies. The researchers hope to identify small molecules that restore this modification process.5
  • A project will test a muscle-targeted protein therapy in mouse models of myotonic dystrophy type 1, in which a protein (called “Muscleblind”) is sequestered and inactivated by a gene defect. The researchers aim to develop an intravenously delivered Muscleblind protein and determine whether this strategy alleviates symptoms of the disease in the mouse model.6
  • A project to develop a novel therapeutic strategy for LGMD type 2B will build on research suggesting that defects in the ferlin proteins disrupt signaling at the neuromuscular junction (the point where a nerve and muscle meet). The researchers will test if a pharmacological compound which acts at the neuromuscular junction can improve disease outcomes in LGMD type 2B in animal models.7
Improved Diagnosis
Identification of the causative gene has led to genetic tests for many types of MD. For other MDs, development of diagnostic procedures has been more difficult. Rapid and accurate diagnosis of the MDs is necessary to both decrease costs associated with the “diagnostic odyssey” and before specific disease treatments can be considered. ARRA-funding is utilizing advances in molecular technology to develop more effective diagnostic methods and better characterize genetic defects in MD.
  • A Challenge Grant will develop new molecular diagnostic tools that will allow rapid, reliable, and cost-effective genetic diagnosis for neuromuscular disorders, including many forms of MD.8
  • A project will characterize mutations causing Duchenne and Becker MD by sequencing large regions of the dystrophin gene. The project will also compile a database to facilitate the identification of subsets of patients who may be candidates for future clinical trials.9
Research Resources
One of the challenges for preclinical development for the MDs is the difficulty of establishing and maintaining good animal models. Mouse models are essential for mechanistic studies and translational research, while large animal studies are needed prior to moving a therapy into clinical trials. ARRA funding is helping to develop and maintain important animal models of the disease.
  • ARRA funding will support the development of a new mouse models of dystroglycanopathies. This aim is part of a large GO grant (also mentioned above) to understand the causes and develop treatments for the dystroglycanopathies.10
  • Funding will allow the expansion of the National Center for Canine Models for Duchenne Muscular Dystrophy (NCDMD), housed at the University of North Carolina. The goal of the NCDMD is to develop and sustain dog models of Duchenne MD and expand collaborations with investigators across the country pursuing therapy development for MD.11

  1. 1RC1NS069234-01 -- New Frontiers in OPMD: Stem Cell Theory of Oculopharyngeal MD -- Pavlath, Grace(contact); Corbett, Anita (GA)
  2. 2R01NS047726-05A2 -- Myoferlin in muscle membrane fusion and repair -- McNally, Elizabeth (IL)
  3. 3R01NS059352-03S1 -- Nucleocytoplasmic Interactions and Dynamics in Emery-Dreifuss MD -- Worman, Howard (NY)
  4. 3R01NS048859-06S2 -- FSHD: Chromatin Structure, Looping, & Expression -- Ehrlich, Melanie (LA)
  5. 1RC2NS069521-01 -- High-throughput genetic & small-molecule screening for therapeutic modifiers -- Campbell, Kevin (contact); Schultz, Peter (IA)
  6. 1R21NS066269-01 -- Intravenous Protein Therapy for Myotonic Dystrophy Type 1 -- Armstrong, Dustin (contact); Weissbart, Richard (MA)
  7. 1R21NS065936-01 -- Preclinical Development of a Novel Therapeutic Strategy for LGMD2B -- Khurana, Tejvir (contact); Lamitina, Samuel (PA)
  8. 1RC1NS069541-01 -- Comprehensive mutation detection for Neuromuscular disorders -- Hegde, Madhuri (GA)
  9. 3R01NS043264-07S1 - Translational Research in the Dystrophinopathies -- Flanigan, Kevin (UT)
  10. 1RC2NS069521-01 -- High-throughput genetic & small-molecule screening for therapeutic modifiers -- Campbell, Kevin (contact); Schultz, Peter (IA)
  11. 3U24NS059696-01A1S1 -- National Center for Canine Models Muscular Dystrophy (NCDMD) -- Kornegay, Joe (NC)

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