Research progress in FSHD

 

Facioscapulohumeral muscular dystrophy (FSHD) is a muscle-wasting condition that causes weakness in the face, shoulders and upper arm muscles. Unlike most inherited muscle-wasting conditions, which are usually caused by a mutation of an important muscle gene, the genetics of FSHD is very complex. FSHD is caused by the production of a protein called DUX4 – which is not normally made in muscle.

There are two types of FSHD (FSHD 1 & 2). Both forms are caused by production of DUX4, but the underlying mechanisms that lead to its activity are different. DUX4 is a so-called transcription factor that switches on genes that are normally not active in the muscle cell. This is toxic for the cell and can lead to its death – resulting in muscle wasting and weakness. You can find more information on the genetics and clinical symptoms of FSHD in our factsheet.


To enable the development of potential therapies, it is essential to increase our understanding of the causes of FSHD and how it affects individuals.

  • MDUK is funding a project from Dr Robert Knight that aims to understand how DUX4 affects muscle stem cells in FSHD. In order to do this, the researchers are developing a zebrafish model of the condition that will be used to test potential drugs.
  • The charity has previously funded research in the laboratory of Professor Jane Hewitt. This research has led to great advances in our understanding of the evolution of the mutated DNA region and the DUX4 gene across species. This information has improved our knowledge of DUX4 function and the development of potential treatments.
  • MDUK also funded research in the laboratory of Professor Peter Zammit that highlighted the effects of DUX4 on muscle stem cells and that this protein prevents muscle repair. The funding has led to significant advances in mapping out the differences between FSHD and healthy muscle induced by DUX4. In addition, a separate MDUK-funded project in the same laboratory has enabled the development of genetically-engineered muscle cells can be used in the lab to test potential therapeutic approaches.


A number of different strategies are being developed to treat FSHD, and some of these are currently being tested in clinical trials.

  • Targeting the genetic cause by blocking DUX4
    • Fulcrum Therapeutics has found that a drug called losmapimod can switch off DUX4 in cells originating from people with FSHD. Losmapimod has previously been tested in 24 clinical trials for multiple indications, including heart and lung disease, so is known to be generally safe. Fulcrum plans to initiate a phase 2b trial testing losmapimod in people with FSHD at clinical sites in the U.S. and Europe in mid-2019.
    • MDUK is funding a project with Dr. Linda Popplewell to develop molecular patches to block DUX4. The molecular patches will be linked to short protein fragments called peptides. It is hoped that these peptides will improve the delivery of the patches into the muscle cells.
    • Professor Scott Harper and his team at Nationwide Children’s Hospital in the U.S. are investigating whether small RNA molecules called micro RNAs can inhibit DUX4 production. They are using a harmless adeno-associated virus to carry the microRNA into the muscle. Initial pre-clinical studies have shown promising results – you can find out more by watching this video.
    • Facio Therapies has screened over 100 compounds in cells grown in the laboratory for their ability to block DUX4 and selected the most promising ones for further research. At the end of 2018, the company announced that one of the compounds being investigated can reduce the levels of DUX4 in a mouse model of FSHD. Facio now plans to do more tests before it can move to a clinical trial in humans in 2021.
  • Increasing muscle mass by blocking myostatin

Acceleron Pharmaceuticals is developing a drug that can potentially increase muscle mass. The drug, ACE-083, works by inhibiting a family of proteins that negatively regulate muscle growth (including the myostatin protein). A phase 1 trial in healthy adults showed ACE-083 was safe and increased the volume of the muscle that it was injected into. A phase II trial in the U.S., Canada and Spain is currently assessing the safety and effectiveness of the drug in individuals with FSHD. Recent interim data from the on-going trial showed ACE-083 was well tolerated and increased the size of the muscle that it was injected into.  Further details on the interim data can be found in our news story.

  • Effects of hormone therapy in men with FSHD

A U.S. based trial is currently assessing the safety and effectiveness of hormone therapy in men with FSHD. Clinical research has shown the combination of the recombinant human growth hormone and testosterone can improve respiratory and muscle function in healthy adults. This is the first clinical study to formally assess if this combination therapy could be beneficial in males with FSHD – find out more details about the trial here.

  • Improving muscle strength with a food supplement

A Phase II clinical trial in Australia is investigating whether a food supplement, creatine monohydrate, can be beneficial for children with FSHD. Creatine works by replenishing energy levels in muscles. Results from previous clinical studies suggests that creatine supplementation is beneficial for people with muscular dystrophies. However these studies weren’t long enough to fully understand the supplement’s efficacy, and none of them focused specifically on people with FSHD.

MDUK provides financial support for the UK FSHD patient registry, an important tool that links patients and researchers. The registry enables the study of the progression or ‘natural history’ of FSHD in detail. This information allows clinicians to identify ways to improve care. For example, in a study conducted at Newcastle University amongst registry participants, it was found that pain in FSHD type 1 is frequent and strongly impacts quality of life. This has highlighted the importance of pain management when treating the condition.

The information collected can also help future clinical trials. It can be used to identify better ways to measure the effectiveness of treatments in studies. It can also accelerate the recruitment of patients, which can sometimes be challenging. Researchers can speed up this process by contacting registry participants who are deemed eligible for a trial.

If you’re interested in finding out more about the registry, you can get in touch with the registry co-ordinator, Ben Porter, by emailing: ben.porter@newcastle.ac.uk

  • Mental Health

MDUK is co-funding a research study assessing whether a type of psychotherapy –known as Acceptance and Commitment Therapy (ACT) – can improve the quality of life for people with muscle conditions, including FSHD. Unfortunately the study is now closed for recruitment, but we’ll keep you updated on its progress. You can find more about ACT therapy in our news story.

  • Activity monitoring

Researchers at King’s College London are running a study to evaluate new ways of measuring active and resting behaviours in people with progressive muscle weakness. If proven useful, these measurement tools could be used in future studies aimed at formulating lifestyle recommendations for people with FSHD and other muscle-wasting conditions. You can find out more in our news story.

To view a pipeline of potential therapies, click here.


If you have any further questions about the latest research in FSHD, please contact our Research Line at research@musculardystrophyuk.org or call 020 7803 4813.

Page updated May 2019.

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