ARRA IMPACT REPORT:
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 are seen in infancy or childhood, while others may not appear until middle age or later. Although myotonic dystrophy is the most common adult form of muscular dystrophy, forms of the disease can affect newborns and older children. Myotonic dystrophy also varies in severity and symptoms. Likewise, limb-girdle muscular dystrophy (LGMD) can strike at any age, affecting the upper arms and legs of children or adults. The most common form of childhood muscular dystrophy is Duchenne muscular dystrophy (DMD), which affects 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.
Molecular Mechanisms of Muscle Diseases
All muscular dystrophies stem from genetic mutations. These errors in the genetic code cause muscle proteins that are critical to proper muscle function to be misprogrammed or produced in insufficient quantities. The pathways that link genetic mutations to disease phenotypes (the outward physical characteristics) 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 muscular dystrophies can lead to a better understanding of these diseases and potential approaches to their treatment or prevention. With ARRA support, researchers explored these molecular pathways through projects that include:
Understanding the structure of the protein that is defective in DMD.2 This project focused on repetitions in the area where most of the mutations responsible for DMD occur.
Examining the role of MBNL, a protein that binds to RNA (molecules that encode genetic information), in myotonic dystrophy and in normal cells.3
Studying the molecular mechanisms involved in misregulating the activity of CUGBP1, a protein family identified in the development of myotonic dystrophy type 1 (DM1).4 Research supported by this grant suggests that strategies to degrade defective RNA might be effective against DM1 and a related disease, myotonic dystrophy type 2.
Developing mouse models that contain molecular defects thought to be associated with LGMD.5 These animals have provided insights into the mechanisms that lead to heart complications associated with LMGD type 2D.
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 small-molecule, cell-based, or gene-transfer approaches that show promise in animal models. NIH ARRA-funded projects related to such therapies included:
Identifying structural changes in the cell nucleus that may activate signals that give rise to Emery-Dreifuss muscular dystrophy,6 a disease that affects skeletal and heart muscle. In addition to contributing to the body of knowledge about the cardiovascular complications that characterize the disease, this ARRA supplement supported a mouse study of small molecules that may become potential drugs.
Demonstrating that a certain type of stem cell can multiply in a tissue culture dish and be manipulated to produce a sufficient number of muscle stem cells for transplantation.7 These findings will serve as the basis for animal studies that may lead to cell-based therapies. Projects also included testing the capability of human muscle stem cells to engraft and improve muscle function in a mouse model of DMD.8 Results using cells produced from two different sources (human embryonic stem cells and human induced pluripotent stem cells [iPSCs] from the skin) were similar. This observation may eventually allow for cells to be taken from a patient, converted to iPSCs, modified to correct the disease-causing mutation, and then to be used to treat the same patient, with limited risk of immune rejection.
Investigating the molecular interactions between an enzyme called nNOS and dystrophin, the protein whose deficiency is the root cause of DMD.9 Published findings include results from a preclinical gene-transfer study suggesting that nNOS expression can be restored in a mouse model of muscular dystrophy.
Testing a method of forcing fluid throughout muscles of the lower limbs as a strategy for delivering gene therapy vectors.10 This ARRA-funded research was conducted as part of the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers program.
Contributing NIH Institutes & Centers
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)