Duchenne muscular dystrophy (DMD) is the most prevalent and aggressive type of muscular dystrophy, affecting one in every 3,500 live male births in the world. It is also one of the most common lethal genetic diseases of children worldwide.
Cutting-edge research, industry-changing model of care improves the lives of patients
A vast amount of research has been conducted in the past 20 years on DMD. Research has explored the use of stem cells to regenerate missing dystrophin in new muscle cells.
Children born with this genetic neuromuscular disorder are typically confined to a wheelchair by age 12 and not expected to live past their early 20s due to cardiorespiratory failure. DMD is characterized by progressive muscle degeneration, affecting all muscles in the body, including breathing muscles and the heart. DMD is caused by a mutated gene encoding the protein dystrophin—an important structural component of the muscles. The gene resides on the X chromosome and, when mutated, deprives the muscles of this essential protein.
Females (XX) are usually carriers of DMD, but are not typically affected by the mutated gene since the second X chromosome acts as a backup to the X chromosome with the gene mutation. Without the second X chromosome, males (XY) are not protected from the mutated gene. In two-thirds of cases, a carrier mother passes on the mutant gene to her son. One-third of cases are due to a spontaneous mutation with no family history.
A vast amount of research has been conducted in the past 20 years on DMD. Research has explored the use of stem cells to regenerate missing dystrophin in new muscle cells. Gene-replacement therapy, using a mini-dystrophin gene, has also proved encouraging in mice models. In addition, several studies are currently under way using small molecules and DNA/RNA analogs to bypass specific types of dystrophin gene mutations. However, to date, no cure for DMD has been proven safe and efficacious.
The only current available treatment option for DMD involves off-label use of corticosteroids (different from anabolic steroids in bodybuilding), which may prolong independent ambulation for up to three years. However, this therapy poses serious adverse side effects such as osteoporosis, mood/ behavioral changes, cataracts, significant weight gain, increases in blood pressure, immunosuppression, and others. No specific FDA-approved treatment yet exists to target the true underpinnings of DMD.
New Era of DMD Research and Care at MassGeneral Hospital For Children
MassGeneral Hospital for Children established a new pediatric neuromuscular (Peds NM) clinic and laboratory in January 2008, both headed by Brian S. Tseng, MD, PhD. The clinic is at the forefront of research and coordinated comprehensive care of patients with DMD and other neuromuscular disorders.
The clinic’s focus is on helping improve and prolong the quality of life of patients currently living with neuromuscular diseases who typically have significant, fragmented, and unmet medical needs. Dr. Tseng and his team are involved in both clinical and scientific research to this end. Already, their findings are paving the way to better long-term care for children with these genetic disorders. This, in turn, will increase the possibility that these patients can take advantage of curative therapies if they become available.
Care for the Living: Clinical Research Improves Quality of Life
Affected children and their families come to the MassGeneral Hospital for Children’s pediatric neuromuscular clinic on Tuesdays. There, neuromuscular specialists, as well as a host of physicians in other disciplines, anticipate and care for patient needs. Team members include pediatric and adult cardiologists, pulmonologists, and neurologists, as well as pediatric endocrinologists, physiatrists, orthopedists, dietitians, orthotists, mobility specialists, physical therapists, and social workers. Despite documentation of the extent to which neuromuscular disorders affect the body as a whole, as well as the patient’s whole family, this broad, interdisciplinary approach to care is surprisingly uncommon. In addition to receiving focused, compassionate care, this population serves as the basis for a number of clinical research initiatives, some of which include:
Scientific Advances Open New Doors in DMD Research
A number of groundbreaking scientific research projects are currently under way with Dr. Tseng’s lab at MassGeneral Hospital for Children. Like the clinical research initiatives, these projects also focus on improving treatment for those living with the disease. Some include:
Desperate for help, many families give their boys with DMD a multitude of untested supplements (e.g. muscle-building powders/ pills) in hopes that it will offer some benefit. The in vitro mini-muscle system is a groundbreaking screening tool for quick and accurate assessment of such compounds/ drugs on DMD muscles. This can help identify not only agents that might benefit the muscles, but just as important, what might also be toxic. Dr. Tseng is the first—and currently only—scientist to use this system to test substances and substance doses on actual contractile function with in vitro human DMD muscles. Already the screening project, called Compound Quest, has shown remarkable results, prompting the exploration of a number of specific clinical trials to prove these findings are valid in boys with DMD. Other forms of muscle disease can also be tested with this approach.
Investigating Modifier Genes
In an NIH-funded study, Dr. Tseng’s lab is investigating modifier genes in the MDX mouse. The MDX mouse is genetically homologous to a boy with DMD. However, even though the mouse has the same gene defect, its muscles are minimally affected. Dr. Tseng’s lab is researching what modifier genes allow the mouse to avoid severe muscular dystrophy. If these genes can be identified, that information can potentially be translated into pathways for human patients to slow the disease. It may be advantageous to find compounds and drugs that can upregulate these favorable modifier genes. The website massgeneral.org/neurology/tsenglab provides further overview of the project.
Understanding the Role of Corticosteroids
Corticosteroids are often prescribed to boys with DMD because of their ability to prolong ambulation—a meaningful benefit to these children. However, the mechanism of action of corticosteroids is not well-understood. Although steroids in general reduce inflammation, scientists believe they benefit patients with DMD in other ways. Dr. Tseng and his lab team are investigating the role of corticosteroids using animal models as well as the in vitro mini-muscle screening tool. If the mechanism can be deciphered, it is possible that better drugs can be developed that provide better benefits with fewer side effects.
Investigating Muscle Images and Muscle Metabolic Characteristics with MRI/MRS
In collaboration with Dr. Martin Torriani, a Mass General radiologist, and Dr. Elise Townsend of Physical Therapy MGH-IHP, Dr. Tseng is launching studies to use magnetic resonance imaging (MRI) and spectroscopy to investigate the imaging and metabolic characteristics of leg muscles over time from the same boys with DMD. This exciting approach is poised to eliminate the need for invasive muscle biopsies and anesthesia. Furthermore, this approach may help diagnose, prognosticate, and track responses to new clinical trial treatments.
Clinical Trials at Mass General
Lab-based research and cutting-edge technology can reach full potential only if new research ideas can be tested and proven in actual human clinical trials. Tapping into the fantastic clinical trials expertise and infrastructure at Mass General, Dr. Tseng is currently organizing DMD clinical trials for this next year and is seeking funding sources (industry, government, and private). Unrestricted gifts to Mass General supporting this groundbreaking work are pivotal for accelerating this critical research.
Since its inception in 2008, the pediatric neuromuscular clinic at MassGeneral Hospital for Children is sparking innovative research and making a true difference in the lives of children and young adults with neuromuscular disorders, including DMD. To be sure, the clinic supports those investigating a cure and better treatments for diseases like DMD. However, it has taken the reins as a national leader and advocate for those families currently suffering from the devastating effects of these disorders. As the clinic and its research data grows, new findings will benefit children currently suffering from these crippling genetic diseases, as well as the quality of life and longevity of patients to come.
|Brian S. Tseng, MD, PhD |
MassGeneral Hospital for Children
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