How does ephedrine improve the symptoms of congenital myasthenia and could it be used for myasthenia gravis?
Following on from previous work, Prof Beeson and his colleagues aim to study the drug ephedrine to find out why it an effective treatment for people with a particular form of congenital myasthenic syndrome. They also aim to find out if the same treatment could be useful for some individuals with myasthenia gravis.
Contents
- What are the researchers aiming to do?
- How will the outcomes of the research benefit patients?
- Grant information
- Further information and links
What are the researchers aiming to do?
Congenital myasthenic syndromes and myasthenia gravis, collectively called myasthenias, are both caused by problems in the signaling between nerves and the muscles. The muscle and nerve meet at a highly specialised site called the neuromuscular junction. When a muscle needs to contract, a signal travels down the nerve and causes it to release a chemical signal called acetylcholine at the neuromuscular junction. The acetylcholine then binds to proteins on the surface of the muscle called acetylcholine receptors which set in motion the chain of events that allows the muscle to contract.
The defective signalling in the congenital myasthenic syndromes and myasthenia gravis causes the muscles to become weak and tire easily. The severity of the conditions varies depending upon the exact type of myasthenia an individual has and ranges from mild with perhaps only the eyelids being affected to very severe or even fatal when the breathing muscles or other essential muscles are affected.
Congenital myasthenic syndromes are inherited and are caused by faults in the genes that carry the instructions for proteins in the neuromuscular junction. Myasthenia gravis, however, is an acquired condition. This means that an individual is not born with the fault but will develop the condition during his or her lifetime. In myasthenia gravis, the body makes antibodies which attack its own proteins, in this case the proteins of the neuromuscular junction. So although the underlying cause of myasthenia gravis and the congenital myasthenic syndromes is different, the end result - a problem with the signal coming from the nerve to the muscle - is similar. This means that by studying one condition, it is also possible to draw conclusions about the other condition.
Prof Beeson previously found that individuals with a form of congenital myasthenic syndrome with a pattern of muscle weakness similar to limb-girdle muscular dystrophy have a fault in the gene that codes for a protein called DOK7. DOK7 is important for clustering the acetylcholine receptors in correctly at the neuromuscular junction. Prof Beeson and his colleagues found that patients with faults in the DOK7 gene respond very well to a drug called ephedrine. In fact they showed that patients who had previously required the use of a wheelchair were able to run and jump following treatment with ephedrine.
It is not, however, clear how ephedrine is able to improve the symptoms of these individuals. Following on from this work, Prof Beeson and his student will investigate why ephedrine works so well in this group of patients. They hope to establish where the drug is acting and what effect this is having on the way the neuromuscular junction functions.
Prof. Beeson and colleagues at the University of Oxford have also discovered that one form of myasthenia gravis is caused by antibodies attacking a protein called MuSK. MuSK, like DOK7, is important for clustering the acetylcholine receptors. Although the cause of these conditions if different, one is caused by a mutation and the other by antibodies, the consequences are the same - the acetylcholine receptors cannot cluster properly. Prof Beeson will therefore also explore whether the myasthenia gravis patients with antibodies against MuSK might respond to treatment with ephedrine as well as the patients with DOK7 mutations. They will initially investigate this using cells grown in the laboratory.
How will the outcomes of the research benefit patients?
This research will show if ephedrine has an effect directly on the formation and stability of neuromuscular junctions, or is working on muscle via some other means. Understanding the mechanism of how ephedrine works at the neuromuscular junction should provide a greater understanding of the implications for its long term use.
Since it is already known that this drug has a dramatic beneficial effect on patients with DOK7 mutations, this research will also tell us how to optimise these effects and whether ephedrine, or similar drugs, could be used to good effect in related myasthenic disorders such as myasthenia gravis.
All drugs have some side effects and researchers aim to reduce the occurrence of these wherever possible. By understanding how ephedrine works and where it acts, researchers may be able to develop other drugs that are slightly different but act in the same way. This could allow then to find a treatment that provide the same beneficial effects of ephedrine, but potentially has less side effects.
Grant information
Project Leader: David Beeson
Location: University of Oxford
Condition: Congenital myasthenic syndromes and myasthenia gravis
Duration: 3 years
Total Project Cost: £94,286
Official Title: Therapy to stabilise synaptic structure for the treatment of both genetic and autoimmune disorders at the NMJ
Further information and links
Read about Prof Beeson's previous research in our research news section
Read about other research we fund
Read about Prof Beeson's other research grant funded by Muscular Dystrophy Campaign
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