Muscular dystrophyBy Amy Johnson

Summary

Recently it’s been shown that relief of muscular dystrophy symptoms is possible using stem cells. In Duchenne muscular dystrophy the protein dystrophin normally found in muscles is absent. Scientists of the San Raffaele Scientific Institute in Milan showed that giving muscles in mice the correct 'recipe' for dystrophin (it's gene) meant that the right protein could be produced. To do this the dystrophin gene was first put into human artificial chromosomes, man-made tools to carry the information and deliver it to muscles. These artificial chromosomes were then put into a specific type of stem cell. These stem cells, known as ‘mesoangioblasts’ were able to successfully integrate into the affected muscles. Interestingly they also became part of the muscles satellite cell pool, which is its factory of new cell production. Increasing the amount of dystrophin in muscles resulted in improvements in muscle function, and some relief of the symptoms. Testing by the scientists showed that these effects continued for 8 months afterwards.

What is the idea behind this study?

There is currently no effective treatment for muscular dystrophy. The disease is caused by changes in the gene responsible for producing dystrophin meaning dystrophin is absent. This leads to symptoms of muscle weakness and progressive muscle loss. A technique to give patients the correct dystrophin gene and therefore protein is not a new idea. Dystrophin is an essential structural protein in muscle. The dystrophin gene itself is large, and a recurring problem is the difficulty transporting such a large piece of DNA to cells. The idea in this study to use an artificial chromosome is a new one, which exploits the ability of artificial chromosomes to carry more information. Prior to this, artificial chromosomes hadn’t been used in this context; however they’re desirable as they don’t interfere with the persons own DNA.

This research group had already shown that the entire dystrophin gene and other necessary elements could be fitted into the artificial chromosome. Here they then looked to see if the HAC slotted into mesoangioblasts, could be used to improve muscle function in mice. These mice were genetically modified to contain no functional dystrophin. This is the animal model most similar to DMD known as the ‘mdx mouse model’. Mesoangioblasts themselves were a good candidate for use, as previous work had shown their ability to differentiate into various cell types including those implicated in DMD: skeletal muscle cells.

What does this research show?

Mesoangioblasts were first obtained from the mice themselves. The artificial chromosome with the dystrophin gene was then slotted in as well as other key genetic ‘checkpoint’ information; for example a protein which fluoresces upon UV light, meaning scientists could see the cells and where they were. Cells then underwent a selection process whereby only the successfully ‘corrected’ ones were reintroduced to the mice.

Three injections into major muscle groups was carried out after exercise and every 3 weeks. The Fluorescence was used to check that the stem cells were actually producing new cells. A technique for protein detection was used to look at how much dystrophin protein was present in the mdx mice compared to normal unmodified mice (with functional dystrophin). Mdx mice produced 25% the amount of dystrophin which equated to enhanced muscle function. Treated mice could run for 50-80% longer than untreated mdx mice. In addition there were fewer damaged muscle cells. Positive effects were seen when corrected mesoangioblasts were transplanted into another mouse model with a more severe form of dystrophy.

What does this mean for patients?

Scientists also looked to see what happened when mesoangioblasts were injected into arteries rather than muscles. It was found that they were able to cross blood vessel walls and contribute to the relief of muscular dystrophy symptoms. They also contributed to the muscle’s satellite cell pool. Both these additional findings help to reinforce the suitability of mesoangioblasts for use in gene therapy.

 It is credible to say that using artificial chromosome mesoangioblasts to administer the correct gene has a basis for therapeutic use in the future.

The technique has been shown to be fairly robust; however, it is only at an early preclinical stage. The effects seen in mice may not be the same in humans. The therapeutic dystrophin protein produced from the gene also needs to be tested, as it may provoke an immune response in patients.

The team is currently carrying out further work to develop mesoangioblasts from patients, which are in early phase human trials. 

Currently a technique known as exon skipping has shown positive effects in patients, but it would not work on a quarter of the genetic mutations associated with DMD. If this artificial chromosome stem cell technique can be refined and if further requirements are met, it may form the basis of a treatment for patients in the years to come.

Further information and links

The full original paper was published in the journal Science Translational Medicine in 2011.  

Muscular Dystrophy Campaign

Funding from the European Community’s Seventh Framework Programme project OPTISTEM supported this scientific work and summary. 


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