Pediatric Neuromuscular Diseases
James Dowling, M.D., Ph.D
- The genetic basis of pediatric muscle diseases
- Using zebrafish to understand the role of Dynamin-2 in human neuromuscular disease
- Insight into myotubular myopathy using zebrafish
- Testing potential therapies in zebrafish
- Targeted therapy discovery and clinical trials for myopathy
- Clinical research efforts for myopathy conditions
Pediatric neuromuscular diseases are a devastating and poorly understood group of genetic disorders for which there are few effective treatments. There are over 40 childhood muscle diseases, known as myopathies, which present at birth with muscle weakness and delayed ability to speak, sit, and walk. Many times children with these diseases are confined to a wheelchair their entire lives, may not be able to perform basic functions for themselves, and may have physical limitations in how they communicate and interact with the external world . Currently there are no cures for these diseases and no drugs that can slow the pace of muscle weakness in these children. Dr. James Dowling, along with PNR&D scientists, is tackling this problem by identifying and understanding the function of the muscle genes and proteins that are involved in the development of myopathies, by developing novel animal models of childhood muscle disease, and by identifying new treatment options for these devastating conditions.
The genetic basis of pediatric muscle diseases
The genetic causes of nearly 40 percent of all inherited myopathies are currently unknown. This makes diagnosis, patient care, determining outcomes, and developing treatment approaches incredibly challenging.
To overcome this hurdle, Dr. James Dowling and PNR&D scientists are using advanced genetic technologies to determine the underlying basis for some of these conditions. Using these approaches, two new genetic causes for types of congenital myopathies have recently been identified. In the first study, a gene responsible for a rare condition called Native American Myopathy was discovered. In the second study, the genetic profile of several family members affected by a form of centronuclear myopathy was determined using a new DNA sequencing technology. This discovery has provided the basis for an NIH-funded research project, where the disease will be modeled and studied so that treatment approaches may be developed.
Using zebrafish to understand the role of Dynamin-2 in human neuromuscular disease
Mutations in a protein called Dynamin-2 (DNM2) have been detected in patients with neuromuscular disorders, including centronuclear myopathy and Charcot-Marie-Tooth disease. Therefore, it is essential to understand how these mutations impact normal neuromuscular development and function in order to gain important information about the disease processes and develop therapies. To accomplish this, PNR&D investigators are enlisting a new animal model – the zebrafish.
Zebrafish are an excellent animal model for numerous neurologic disorders, and are easily manipulated to examine the effects of various genetic alterations on normal tissue development and performance. Although little is known about role of DNM2 in normal zebrafish, PNR&D investigators have recently determined that this gene is important for neuromuscular development. These findings, along with results from current efforts to determine how the mutations affect this function, will provide important information about why muscle function is impaired in neuromuscular conditions with DNM2 mutations so that much-needed therapies can be developed.
Insight into myotubular myopathy using zebrafish
The scientists of the PNR&D are beginning to unlock the biological mechanisms of myotubular myopathy, a severe inherited muscle disease whose origins are poorly understood. To study myotubular myopathy, Dr. James Dowling has developed an animal model of the disease using zebrafish. By generating a strain of zebrafish with the characteristics of the myotubular myopathy, he can study the mechanisms and presentation of the disease in a new way. Recent results indicate that these zebrafish have unique abnormalities in a section of the muscle called the tubulorecticular system, which is vital for normal muscle contraction. Similar changes have also been recently observed in muscle from human patients with myotubular myopathy, corroborating the importance of the zebrafish findings. The discovery that the tubuloreticular system is compromised in myotubular myopathy links it to other known conditions with similar defects, opening the door to studies into therapeutic options which might be effective in patients with a variety of myopathies.
Testing potential therapies in zebrafish
There are no cures or effective treatment options for most muscle diseases. Because of this, one of the more exciting projects in the PNR&D is the use of large-scale drug screens to identify new therapies for muscle diseases. Several models of muscle diseases in zebrafish have been developed in the laboratory, which can be used to test numerous drug treatments by simply adding test compounds to the water they swim in. Zebrafish breed and develop rapidly, allowing investigators to test hundreds of compounds with ease. Using zebrafish muscle disease models, Dr. James Dowling and PNR&D investigators are currently testing a panel of 1,200 FDA-approved compounds for their ability to improve motor function. By focusing on drugs that already have FDA approval, these screens have the potential to accelerate the identification and delivery of much-needed therapies to patients.
Targeted therapy discovery and clinical trials for myopathy
Insight into muscle disease mechanisms and pathways provides targets for the design of potentially effective therapies for these conditions. Using zebrafish, Dr. James Dowling and PNR&D investigators discovered that there is abnormal oxidative stress in a zebrafish model of a pediatric muscle disease called core myopathy. When the diseased zebrafish were treated with antioxidants, however, there were drastic improvements in the movement abnormalities associated with the condition. These observations were validated in muscle cells derived from patients with core myopathy through a collaboration with Dr. Ana Ferreiro in Paris, France. Together, these exciting findings provided support for a clinical trial for the antioxidant N-acetylcysteine in patients with core myopathy, which is planned in France.
Targeted therapy development has also been successful for a specific type of muscle disease called centronuclear myopathy. Zebrafish models were again used to model the disease, which allowed Dr. James Dowling and PNR&D investigators to determine that neuromuscular junctions did not function properly in the disease. Based on this knowledge, the zebrafish were then treated with a drug called mestinon that is known to improve neuromuscular junction function. The improvements observed in the zebrafish following treatment were validated in a mouse disease model, which confirmed that mestinon improved both endurance and strength. Based on these data, a clinical trial examining mestinon in centronuclear myopathy patients is in progress. This is the first clinical trial for any congenital myopathy to date.
Clinical research efforts for myopathy conditions
Clinical research to understand the characteristics of muscle disorders is also important to gain insight into the disease and improve patient care approaches. Dr. James Dowling is part of an ongoing effort to identify new clinical features that are associated with these conditions, and use these findings to establish better ways to diagnose, and potentially find ways to treat, myopathies. Recent accomplishments on this front include a broad-reaching standards-of-care document that includes recommendations for patient care that are being implemented across the country.
