Using gene therapy, a team of researchers from the University of Tokyo has improved the strength, motor skills and life span of mice with two different neuromuscular diseases. The study raises hope that one day, similar therapies could be used to treat humans with a range of muscular disorders such as muscular dystrophy and amyotrophic lateral sclerosis (ALS).
Neuromuscular disorder is an umbrella term that encompasses many different diseases that either affect the muscle directly, resulting from problems with the muscle structure, or indirectly, resulting from faulty signaling between nerves and muscle. This signaling occurs at the neuromuscular junction (NMJ), which is the interface between neurons and muscle fibers.
Previous work has found that a protein called Dok-7 is pivotal for the proper formation of the NMJ. Certain neuromuscular diseases, such as familial limb-girdle myasthenia, are known to be caused by a defective DOK7 gene. This mutant gene results in the production of a faulty Dok-7 protein, which prevents the NMJ from forming properly. Consequently, patients experience progressive muscle wastage that often causes the individual to be wheelchair-bound and have breathing difficulties. Sometimes, the muscle loss can be so severe that patients die from a weakened heart. Similarly, mice missing a functional DOK7 gene are severely underweight and die at a young age.
To find out if gene therapy could improve the symptoms of mice with a model of familial limb-girdle myasthenia, researchers engineered a virus to contain the normal human DOK7 gene. They then injected this virus directly into the muscle of the diseased mice, which shuttled the gene into the recipients’ cells.
Within just seven weeks, the mice gained weight and became stronger. Further examination revealed that the mice had significantly larger NMJs than mice that had not received treatment, and that their cells were churning out the Dok-7 protein. The mice also had an increased life expectancy and normal scores on motor skill tests.
To take this further, the researchers tried their engineered virus on a mouse version of a different neuromuscular disorder, called Emery-Dreifuss muscular dystrophy (EDMD). This disease, which is once again caused by defective NMJs, is characterized by slowly progressive muscle wasting and weakness.
The researchers found that once again, the size of the NMJs increased when compared with control mice. Moreover, they also saw positive effects on life span and muscle strength. However, the mice did not recover completely because EDMD also affects the hearts of sufferers, which was not addressed by the therapy.
Due to the fact that neuromuscular diseases are caused by a number of different mutations, this therapy is not “one size fits all.” However, the research is encouraging and it may be that DOK7 gene therapy could treat at least some of them. The researchers are therefore continuing this work by looking at other neuromuscular diseases in mice to find out which ones this gene therapy may benefit.