Saturday, August 27, 2011

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.


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

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:

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

Monday, August 15, 2011

Big Stories - No Takers

It is perplexing how to get today's news organizations to pick up and share stories with their readers.....As a small, non-profit we have helped to fund research that is making major breakthroughs yet, the Seattle public has no idea that this work is being done in their own backyard.  Last year researchers here (at the Hutch & UW) in collaboration with scientists in the Netherlands & Rochester, NY made a huge breakthrough in Facioscapulohumeral (FSH) Muscular Dystrophy research - it made news in New York, being a featured story in the New York Times yet, Seattle readers were left in the dark.

It is amazing the progress we have made - functioning from our home on a "all volunteer" basis without getting the support from our local press.  Yet, our organization Friends of FSH Research ( has been able to raise over a million dollars for FSH research and has helped launch pilot projects which generated new data, their findings which earned the respect and funding from the National Institutes of Health.

Facioscapulohumeral (FSH) Muscular Dystrophy, today believed to be the most common form of Muscular Dystrophy,  (who knew that there are more than one form?) has received little research support in the past from the existing funding sources.  This condition impacts the lives of those affected throughout their life span - causing a weakening then ultimately the death of the muscles of the upper back, upper arms and face. Eventually the muscle destruction extends into the muscles of the lower legs and trunk .... it is an unforgiving condition.  Not a sexy condition, not one which attracts media attention... one often overlooked, forgotten.

Friends of FSH Research proves the "Power of One" - one family, one love for their child.  We would not have been able to succeed without the internet, social media and the community.  This is one story that has not yet been helped by traditional media - though I am still hopeful that one day they will pick up our story for I think it is one worthy of telling.

Friday, August 5, 2011

FSHD and Standing Frame Exercise

FSHD and Standing Frame Exercise : Progressive Muscular Dystrophy

Standing Frame Exercises
People with FSHD may also benefit from exercises carried out using the support of the system known as a standing frame, which is designed to support a person with mobility restrictions stand and then remain in a standing position. potential advantages of using a standing frame include preserving some range of motion, enhancing bone strength, growing blood circulation and realigning the position within the inner organs. Other possible advantages include worry reduction and lowered risks for any form of abnormal muscle and tendon shortening known as contracture.

Monday, August 1, 2011

Generosity of Strangers and Old Friends - Amazing Grace

THANK YOU!! Spent the weekend sharing our story with artists at the Bellevue Art Festival. I am touched that so many individuals were willing to donate their artwork to us for our January auction. The generosity and kindness we have received has been amazing ... although the work of procurement is certainly not an easy one, I am forever grateful.
I will start posting pictures and website links of the artists over the coming weeks - Please check out their artwork!