The NICHD is one of many federal agencies and NIH institutes working to understand muscular dystrophy (MD).
The NICHD's Developmental Biology and Structural Variation Branch (DBSVB) supports basic and clinical research on normal and abnormal development that relates to the causes and prevention of structural birth defects, as well as research training in relevant academic and medical areas. Among the Branch's high-priority research areas is basic research to advance understanding of the biochemical, molecular biologic, genetic, and cellular mechanisms of embryonic development.
DBSVB-supported research on MD includes work on dystroglycan, a protein that allows nerve cells to spread along the spinal cord in developing mammals. This research has generated new information about MDs and associated nerve and muscle degeneration that are caused by dystroglycan-related gene mutations. (PMID: 23217742)
The NICHD's Intellectual and Developmental Disabilities Branch (IDDB) sponsors training in muscle biology and MD research aimed at preventing and ameliorating intellectual and related developmental disabilities.
Past and present IDDB-supported research on MD includes drug therapy to help alleviate the symptoms of myotonic MD as well as several studies focused on Duchenne MD (DMD). These include the following:
- Studying the effects of glucocorticoid treatment—the current standard of care for DMD—on the immune system to help researchers better understand why the immune system blocks gene correction methods.
- Developing a two-tiered newborn screening: examining creatine kinase (CK) levels in the blood and then testing for gene mutations in infants with CK levels already determined to be elevated. This helps to correct for false positives and to predict DMD gene mutations. (PMID: 22451200)
- Successful application of exon-skipping on canines. Genetic researchers treated dogs with canine X-linked MD, which is similar to DMD in humans. "Exon-skipping" uses synthetic DNA-like molecules called antisense to skip over the parts of the gene that block the creation of dystrophin. Because the gene's mutation could affect any of its 79 exons and sometimes more than one exon at a time, scientists created a "cocktail" of antisense called morpholinos to ensure that all of the mutations are covered. This treatment has the potential to benefit between 80% and 90% of DMD patients.
IDDB's support of MD research also produced this finding:
- Understanding the Genetic Cause of Limb-girdle MD
Over a decade ago, scientists identified a specific genetic location associated with LGMD. However, it proved difficult to identify which specific genes were involved and exactly how genetic mutations act on the body in the development of LGMD. Scientists analyzed detailed genetic information from nine families affected by the most common type of LGMD. The researchers discovered a group of mutations in individuals with LGMD. All these mutations resulted in increases in a specific type of protein that has also been associated with other conditions, including Parkinson's disease. Increases in one form of this protein resulted in toxic effects on muscle cells, leading to some of the symptoms of LGMD. Researchers are now looking at the possibility of developing treatments that could be administered early, before the damage from LGMD begins. (PMID: 22366786)
In addition, the NICHD's National Center for Medical Rehabilitation Research (NCMRR) leads two programs that support research for people with MD.
- The Spinal Cord and Musculoskeletal Disorders and Assistive Devices (SMAD) Program focuses on developing and supporting the application of devices to improve patients' interactions with their environment and to restore or enhance their capacity to function in that environment. The program supports the development of rehabilitation technology such as prosthetics and wheelchairs as well as applied research in biomechanical modeling and other topics that aim to enhance mobility, communication, cognition, and environmental control. Researchers recently studied the signaling response from transforming growth factor b (TGFb), a protein that plays a role in the development of many conditions, including heart disease and MD. They discovered that decreasing signaling from TGFb lessens skeletal and heart muscle malfunction.
- The Behavioral Sciences and Rehabilitation Technologies (BSRT) Program leads the NCMRR's efforts to support research for developing assistive technology aimed at helping individuals with disabilities perform daily activities. The behavioral science aspect of this program conceptualizes, initiates, and supports scientific efforts designed to advance knowledge relevant to the role of the behavior of individuals with physical disabilities. The rehabilitative engineering portion of the program develops and supports the application of engineering and bioengineering principles to study the habilitation of individuals with disabilities.
Recent NCMRR advances in MD research include the following:
- Genetic Mutation Leads to Faster Disease Progression in DMD Patients
DMD disease varies substantially in severity and response to treatment, which suggests that other genes or environmental factors can modify the effects of DMD. To explore this theory, researchers used two different groups of DMD patients to identify additional genes that increase disease severity. They found a mutation in the SPP1 gene that caused greater muscle weakness and more rapid disease progression. Of patients without this mutation, 20% could still walk at age 14. Of those with the mutation, none could still walk at this age. The SPP1 mutation occurs in about 35% of DMD patients. Identifying it not only helps researchers understand how DMD and other muscular dystrophies progress, but also could be important in developing treatments for DMD. (PMID: 21178099)
- In Long-term Animal Model of DMD, Losartan Reduced Mortality and Improved Heart Function
Losartan, a drug used to treat high blood pressure, has shown positive results on muscle function and strength in short-term animal models of DMD. The next logical step was to conduct longer-term studies in animals. In addition, previous animal studies have not determined losartan's impact on cardiac function. Identifying cardiovascular problems is especially important because heart failure is a common cause of death in young men with DMD. Scientists examined the effects of long-term losartan treatment in mice with DMD. Researchers found that after long-term treatment with losartan, 88% of treated mice were alive, compared with only 44% of untreated mice. While cardiac muscle function was significantly preserved in the treated mice, there appeared to be no change in the weight, morphology, and function of skeletal tissue. These findings suggest that losartan could be an important prophylactic treatment for heart disease associated with DMD but that the drug may not have a positive impact in the long run on DMD-associated skeletal muscle disease. (PMID: 21731628)
- Study Offers New Insights for MD Therapy
MD is caused by mutations in genes that encode a complex of proteins associated with dystrophin (a protein involved in maintaining the integrity of muscle). People with MD also develop diseases of the heart muscle that enlarge the heart and make it more rigid than normal. Researchers have observed that signaling from TGFb is often increased in humans and in animals with MD. However, it was unclear whether this type of TGFb signaling actually causes abnormalities in the muscle. Understanding the processes that contribute to muscle damage may point the way toward new treatment approaches. Using a genetically altered fruit fly that develops progressive muscle and heart dysfunction similar to human MD, the researchers studied whether TGFb signaling drives the progression of MD. They found that TGFb signaling occurred immediately adjacent to the sites of exercise-induced muscle injury. By genetically decreasing the signaling, researchers were able to lessen skeletal and heart muscle malfunction. The study suggests that scientists should explore trying to develop treatments that target the TGFb pathway. (PMID: 21138941)
The NICHD is also active in the following projects that are related to MD research:
- The goal of the Wellstone Muscular Dystrophy Cooperative Research Centers (MDCRCs), supported through the IDDB, is to foster the translation of new scientific findings and technological developments into novel treatments for MD. The NICHD funds two of the MDCRCs, one at Research Institute of Nationwide Children's Hospital and one at Boston Biomedical Research Institute. The IDDB also funds opportunities for career development programs among junior investigators affiliated with the NICHD-funded MDCRCs. Three current career development programs provide support for MD investigators in laboratory research and patient-oriented research with the goal of increasing the number of researchers and the quality of research and training.
Recent findings from studies of mice and human muscle cells indicate that an existing drug, dantrolene, can amplify the effectiveness of new drugs currently in clinical trials to treat DMD by increasing dystrophin levels. (PMID: 23241744)
- The IDDB-funded NICHD Brain and Tissue Bank for Developmental Disorders aims to advance the research of developmental disorders, including MD. The objective of this human tissue repository is to systematically collect, store, and distribute brain and other tissues for research dedicated to the improved understanding, care, and treatment of individuals with developmental disorders. The bank has a separate website for tissue donors and their families, as well as a donor registry.