Collaborating Research Teams - Progress toward FSH Treatment

Two research teams make steps towards a treatment for FSH

Two research papers published in the past month by researchers in Italy and the US have shown that it is possible to reverse the symptoms of facioscapulohumeral muscular dystrophy (FSH) in a mouse model using a gene therapy approach. The techniques used may also be applicable to other dominantly inherited muscle conditions such as myotonic dystrophy, oculopharyngeal muscular dystrophy (OPMD), Charcot-Marie-Tooth disease and some types of limb girdle muscular dystrophy, congenital muscular dystrophy and congenital myopathy.

Contents:

Who are the Researchers?  

Joel Chamberlain PhD at the Division of Medical Genetics, University of Washington, Seattle, Washington and Davide Gabilini at the Division of Regenerative Medicine, Milan, Italy.

Original publication:  

AAV6-mediated Systemic shRNA Delivery Reverses Disease in a Mouse Model of Facioscapulohumeral Muscular Dystrophy

• http://www.nature.com/mt/journal/vaop/ncurrent/abs/mt2011153a.html
• Funding for Joel Chamberlain's work provided by Friends of FSH Research and the MDA
• What did the research show?
• What does this mean for FSH patients?
• What about other conditions?
• Further information and links

Background information

FSH is caused by changes to a region of DNA on chromosome 4 called D4Z4 that has the same piece of DNA code repeated many times. In healthy individuals the number of repeats varies between 11 and 100. People with FSH have less than 11 repeats.  Until recently scientists have struggled to understand how this caused the symptoms of the condition.

Recent research demonstrated that the repeated section of DNA contains a gene called DUX4 and the reduction in the number of repeats on D4Z4 changes the way this piece of DNA is folded. This results in the DUX4 gene being switched on and the DUX4 protein being produced which is toxic to the muscle. 

Although this is currently the most widely accepted theory about the underlying mechanism causing FSH, previous research has also shown that neighbouring genes such as one called FRG1 may also be involved. It has been proposed by some researchers that FRG1 is switched on in FSH which is toxic to the muscles. The importance of FRG1 in causing the symptoms of FSH in humans is still controversial though, because it hasn't been proven beyond doubt that it is involved.

What did the research show?

This research took advantage of natural processes in the body which regulate which genes are switched on and which are off.  When a gene is 'switched on', RNA 'photocopies' of the gene's code are made. The RNA moves outside the nucleus where they direct the manufacture of proteins. DNA can be thought of as a recipe book in the library that you can't take out. RNA is a photocopy of a recipe that you can take home to cook something in your kitchen (making the protein).

The new potential therapies involve switching off a gene so that the RNA copy is not made. This is called "RNA interference" or "gene silencing". It involves introducing into the cell tiny pieces of genetic material called "micro RNA" or "short hairpin RNA" that are designed to specifically switch off a particular gene. Although the strategy was similar in the two studies, the design of the microRNA was different.

Both research groups tested their new potential therapy in the only available mouse model for FSH - the FRG1 mouse. These mice have increased levels of FRG1 and develop muscle wasting and weakness.

Adeno-associated viruses (AAV) were used to deliver micro RNA that was designed to switch off the FRG1 gene into the cells of the mice. AAV is currently the most attractive candidate for gene therapy because it is not known to cause any severe disease in humans and is capable of infecting many different cell types including muscle cells.

Both studies reported that after the RNA interference treatment, the mouse muscles not only looked healthier under a microscope but their muscle size and strength was improved. For example in one study they measured how long the mice could run on a treadmill before they got tired. Untreated 12-week-old mice could only run for about 15 minutes whereas those that had been treated with the RNA interference were able to run for almost 25 minutes; on a par with healthy mice. One of the studies also included extensive toxicity monitoring and they concluded that the treatment appeared to be safe in mice.

What does this mean for FSH patients?

This research is exciting because it proves the principle that RNA interference is a promising therapeutic approach for FSH. One of the challenges of treating any muscle condition is to deliver the drug to all of the muscles of the body which make up a large proportion of our body mass. These studies were able to show that it is possible deliver the RNA efficiently to the muscles using a virus and this had a positive effect on muscle function.

Whether FRG1 is the correct target for a FSH therapy is still uncertain and more research is required to understand its role. However, the authors of these studies said that this technology could easily be applied to other target genes such as DUX4. Researchers are currently working to develop a DUX4 mouse model that would allow this to be tested.

RNA interference is very new technology and although there have been promising results from animal models, in particular for neurodegenerative conditions, no drugs have reached the clinic yet. Therefore, it may be several years before it is ready for testing in patients.

This strategy is similar to the exon skipping that is in clinical trial for Duchenne muscular dystrophy. Both strategies involve delivering small pieces of genetic material to change the way genes function. The difference is that for Duchenne muscular dystrophy a gene is repaired, whereas with for FSH a gene is switched off. The recent positive results in the Duchenne clinical trials will spur on researchers working on this strategy and inform them on ways to move this therapy forward to the clinic.

What about other conditions?

It is only in recent years that scientists have started to understand more about how genes are switched off  which has opened up the prospect of treating conditions that result in the production of harmful RNA or protein.

RNA interference could potentially be used to treat many other muscle conditions where the faulty gene has toxic effects on the muscle or interferes with the functioning of other healthy genes. These conditions are inherited in an "autosomal dominant" way, which means that only one faulty gene, inherited from either parent, is required to cause the condition.

Examples include myotonic dystrophy, oculopharyngeal muscular dystrophy (OPMD), Charcot-Marie-Tooth disease and some types of limb girdle muscular dystrophy, congenital muscular dystrophy and congenital myopathy. However, each affected gene will need to be looked at on a case by case basis, and researched in the laboratory before it can decided if it could possibly be amenable to RNA interference.

Considerable research has already been done in a mouse model of myotonic dystrophy using small pieces of DNA. Although closely related, that research was not the same as RNA interference. It involved blocking the interaction between RNA and proteins, rather than switching off the production of the RNA in the first place, which would be the case with RNA interference. So RNA interference adds another line of attack to the potential therapies currently being researched for myotonic dystrophy.

Article cited from: http://www.muscular-dystrophy.org/

Funding for Davide Gabelini's work provided by Muscular Dystrophy Campaign, UK