Research Round-up MDs & NMDs

Muscular Dystrophy Australia supports people with any one of more than 60 neuromuscular conditions. We have already published updates for some of the more common conditions and this week we have the research highlights for the other conditions we cover.

Myotonic dystrophy
Clinical trial first
In June the first clinical trial tackling the cause of myotonic dystrophy was started. The phase 1 trial by Isis Pharmaceuticals tested ISIS-DMPKRx — a drug designed to reduce the production of toxic molecules in the cells of people with myotonic dystrophy type 1. This new drug uses so-called “antisense” technology which involves small pieces of genetic material which are designed to specifically bind to, and block the faulty genetic instructions inside the cells of people with myotonic dystrophy. This approach has been shown to reverse symptoms of myotonic dystrophy in a mouse model of myotonic dystrophy.

Only healthy volunteers were included in this trial – this is standard practice for phase 1 trials. The trial has given the company the first information about the safety of the drug in humans. It was announced this week that the subsequent trial (phase 1/2a) has started recruiting. This trial will include 36 people with myotonic dystrophy aged between 20 and 55 years and will be conducted at seven different locations in the USA. The participants will receive one of four different dose levels of ISIS-DMPKRx or a placebo for six weeks with the aim of testing the safety of the drug and finding the best dose for future trials.

The start of the ISIS-DMPKRx trials is encouraging news because targeting the root cause of myotonic dystrophy is the ultimate goal for an effective treatment. The condition affects many different systems in the body besides the muscles and it is hoped that a therapy such as this will be able to alleviate many of the symptoms that affect people with myotonic dystrophy.

More details about the Isis trial for myotonic dystrophy.

Can psychology help?
A trial named OPTIMISTIC has started recruitment in Europe. Researchers aim to recruit nearly 300 people with myotonic dystrophy to determine how effective sessions of personally tailored cognitive behavioural therapy are on levels of fatigue, physical activity and quality of life compared to standard patient care. See below for the results of a similar study already carried out for FSHD.

Insights into myotonic dystrophy type 2
Scientists in Florida have, for the first time, studied the 3D structure of the genetic defect that causes myotonic dystrophy type 2 (DM2). This allowed them to design drug candidates with potential to treat the condition. The drug candidates proved effective in cells grown in the laboratory but further testing will be required before proceeding to a clinical trial can be considered.

Similarly, researchers at the University of Illinois recently reported that they have designed drug candidates which are effective in DM2 cells grown in the laboratory. Future studies will test the safety and effectiveness of these substances in fruit flies and mice.

Facioscapulohumeral muscular dystrophy (FSHD)
Drug screen
Researchers at the University of Minnesota have screened 44,000 small, drug-like molecules for their ability to protect muscle cells from the toxic DUX4 protein that is present in people with FSHD. They found 54 molecules that show promise for further investigation.

Managing fatigue
A study in the Netherlands involving 57people with FSHD has shown that both aerobic exercise and cognitive-behavioural therapy (CBT) reduce chronic fatigue. The patients who took part in sessions of CBT with a therapist also had an increase in physical activity, sleep quality and social participation. After the 16 weeks of supervised sessions, the participants were followed up for a further 12 weeks and it was found that the improvements in quality of life were sustained. This is not to say that the fatigue is ‘all in your head’; the CBT involved learning practical ways of managing the very real fatigue that people with FSHD experience in their daily life.

New FSHD trials
San Diego based biotech company aTyr Pharma has started a clinical trial to test a drug called ATYR1940 in people with FSHD in France and the Netherlands. Little information is publicly available about the drug, but it is thought that the drug’s anti-inflammatory properties may be of benefit in FSHD. More information about the aTyr Pharma trial.

Researchers in Denmark have started a trial to explore whether high intensity exercise training is safe and beneficial for people with FSHD.

Limb girdle muscular dystrophies
Gene therapy
Researchers in North Carolina have tested two different gene therapy strategies for limb girdle muscular dystrophy type 2I (LGMD 2I) in mice. The technique involved introducing a healthy copy of either the FKRP gene (which is mutated in LGMD 2I) or another gene thought to do a similar job – LARGE. The latter may also be applicable to types of congenital muscular dystrophy caused by mutations in the LARGE gene. Results are promising but more work is required before it can be tested in patients.

Researchers in Ohio, USA have tested a gene therapy technique for conditions caused by changes to the myotilin gene — LGMD type 1A and myofibrillar myopathy. In these conditions abnormal myotilin protein is toxic to the muscle cells. In this study, viruses were used to deliver small pieces of genetic material called ‘microRNAs’ which were designed to bind specifically to the abnormal myotilin and prevented the toxic protein being made. As a result the mice had improved muscle health. This research is promising, not only for LGMD1A, but also the other type 1 LGMDs that are dominantly inherited.

Better monitoring of muscle health
An international team of researchers have evaluated a sophisticated scanning technique for measuring the health of muscle in people with LGMD 2I. This “Dixon MRI” is more accurate and objective than the currently used MRI scans and could be useful for diagnosis, measuring the progression of the condition, and monitoring outcomes in clinical trials.

Clinical trial for congenital muscular dystrophy
Swiss pharmaceutical company Santhera announced in July the start a clinical trial of a drug called omigapil in children with congenital muscular dystrophy (CMD). Twenty participants, aged from five to 16 years of age with Ullrich CMD or merosin-deficient CMD (MDC1A) will take part in the trial for 12 weeks.

The study (called CALLISTO) will take place in the USA and will assess the safety, tolerability and pharmacokinetics of omigapil. Pharmacokinetics involves measuring how much of the drug reaches the blood stream, which will help to determine the optimal dose for a subsequent clinical trial.

Omigapil is an oral drug which was originally developed for the treatment of neurological disorders including Parkinson’s disease and amyotrophic lateral sclerosis (ALS). It is thought to work by preventing cells dying. Omigapil does not target the primary genetic cause of CMD and so it cannot be considered a ‘cure’, but testing in a mouse model of MDC1A has shown that it may be able to reduce the severity of symptoms. Read more about the omigapil for CMD trial.

Encouraging clinical trial results for oculopharyngeal MD
The results of a clinical trial have shown that transplanting cells from unaffected muscles into the throat may help with the swallowing difficulties that affect people with oculopharyngeal muscular dystrophy (OPMD).

OPMD is a rare type of muscular dystrophy which is unusual because it primarily affects two small muscle groups — those used for swallowing and the muscles around the eyes — and the other muscles of the body are generally spared.

A clinical trial was embarked on in Paris, France to transplant immature muscle cells (myoblasts) from the neck or upper thigh, into the throat. In the trial, twelve people with OPMD underwent an operation called a “cricopharyngeal myotomy”. OPMD patients often have this procedure to release contracted scar tissue in the throat and improve swallowing. During this procedure the trial participants also had their own myoblasts injected into the pharynx.

It was found that swallowing improved for all twelve trial participants and this remained stable for two years. Longer term follow-up is also ongoing and the results appear to be positive, whereas people with OPMD who only have the cricopharyngeal myotomy surgery generally initially improve but then deteriorate.

However, it must be remembered that this was only a small trial and due to the rarity of the condition it was not feasible to include a placebo group for comparison — that is, patients who did not receive the myoblast injections. Valuable information on the best way to perform the transplant was gained in this study which will be used to plan a larger trial to assess in more detail the benefit of myoblast transplantation for OPMD before it can be brought into clinical practice.

New myotubular and centronuclear myopathy research
Researchers in France have reported on a potential way to treat some types of centronuclear and myotubular myopathy. This relates to the discovery that two of the genes causing these conditions —myotubularin and dynamin 2—appear to interact with each other in muscle cells.

They found that the myotubularin protein (which is lacking in children with X-linked myotubular myopathy) is normally an inhibitor of dynamin 2. Increased levels of dynamin 2 protein are therefore found in the muscles of children with myotubular myopathy.

Interestingly, changes to the dynamin 2 gene itself also cause a milder type of centronuclear myopathy. Previous studies have shown that the changes to the dynamin 2 gene that cause centronuclear myopathy lead to increased activity of the protein. So it appears that having too much dynamin 2 is toxic to the muscles.

The researchers then reduced levels of dynamin 2 in mice that are a model of myotubular myopathy and found that these mice had much improved muscle function and a longer life span. So the researchers are now searching for dynamin 2 inhibiting drugs that are suitable for testing in humans.

It is hoped that this research might lead to a treatment for myotubular myopathy and one type of¬ centronuclear myopathy. People with another neuromuscular condition — Charcot-Marie-Tooth disease type 2M, which is caused by different changes to the dynamin 2 gene — might also benefit from this research and the researchers suggest that it may also be applicable to some other neuromuscular disorders.

Improving the diagnosis of rare diseases
Over 180 of the world’s leading organisations including research institutions, hospitals and biotech companies have formed an alliance to enable responsible, secure, and effective sharing of genetic and clinical data.

The human genome is made up of over 3 billion “letters” of genetic code contained within our DNA. Genome sequencing involves determining the order of all of these letters. More and more people are having their genome sequenced as the cost falls: new genome sequencing technology allows the whole genome to be sequenced for around $1500. However, interpreting the resulting data is highly complex and requires collaboration amongst world experts.

This is especially true for very rare conditions where there might only be a handful of people with the condition worldwide. Sharing of information will allow patients with similar symptoms and similar genetic variations to be matched up, thus helping to identify the culprit gene. The sharing of data will also increase understanding of diseases and advance research towards treatments for rare diseases as well as more common ones such as cancer.

Although there is no specific cure or treatment available for most rare genetic conditions, a precise diagnosis can lead to better management of the condition and allow families to plan for the future with the help of genetic counselling.

Thirteen Australian organisations including The Murdoch Children’s Research Institute and the Royal Children’s Hospital have joined the Global Alliance for Genomics and Health.

News bites
With so many different types of neuromuscular conditions it is not possible to report in detail on every piece of news. Below are some snippets of news from this year, if you would like to know more please contact us:
• Two new genes (called SUN1 and SUN2) responsible for causing Emery-Dreifuss MD have been identified, bringing the number of genes known to cause this condition up to eight. In a separate research study, a possible way to treat the heart problems experienced by people with EDMD has been discovered.

• A group of researchers in China have identified that a protein called IL-9 plays a role in the development of symptoms in an animal model of myasthenia gravis. This discovery may lead to the development of new treatments which block the activity of this protein.

• A phase 2 clinical trial of the drug rituximab in adults with myasthenia gravis has started in the U.S. This drug suppresses a specific part of the body’s immune system and is already used to treat rheumatoid arthritis and other disorders.

• Italian scientists have unravelled how SEPN1 mutations cause the muscle diseases minicore myopathy and congenital muscular dystrophy with rigidity of the spine (RSMD) and suggested a possible route to develop a treatment.

• Addex Therapeutics has announced that it is continuing preclinical development of a drug called ADX71441 for Charcot-Marie-Tooth disease (CMT) type 1A. Initial experiments have shown that the drug could lower levels of toxic PMP22 protein and potentially delay the progression of the disease. It is hoped that this preclinical development will lead to a clinical trial of the drug in the future.

• German researchers have found that in a growth factor called neuregulin-1 which is normally produced by nerve cells could be the basis for a possible treatment for CMT1A. Administering this growth factor to a rat model of the disease improved symptoms. However, neuregulin-1 cannot safely be given to humans so the scientists now plan to design drugs that imitate its action.

• More genes have been found for CMT bringing the total to more than 70 genes

• Danish researchers have found that people with polymyositis and dermatomyositis tend to have a higher risk of heart disease than the general population. It is not known why this is the case but long-term glucocorticoid treatment, physical inactivity and persistent low grade inflammation in the body have been implicated. More research is required as this was only a small study and information on how to manage this increased risk is needed.

• An international team of researchers from Germany and the USA has developed a mouse model for Ullrich congenital muscular dystrophy caused by dominant mutations. The development of animal models is a key part in identifying and testing potential therapeutic approaches.

• BioBlast Pharma has started a phase 2 clinical trial in Israel and Canada of a drug called Cabaletta which is based on the sugar trehalose. It is hoped that it will prevent the clumping of abnormal proteins that occurs inside the cells of people with OPMD. Initial results released in September 2014 showed that the drug appears to be safe. The trial aims to test Cabaletta in 60 people with OPMD for 28 weeks in order to determine if it is safe and if there is any indication that it slows the progression of the condition.

• Pharmaceutical company Biomarin has purchased from Repligen the rights to develop RG2833 (and other similar drugs) which are in early stage development for the treatment of Friedreich’s ataxia. RG2833 is a histone deacetylase (HDAC) inhibitor, and it is hoped that it will be able to increase production of the frataxin protein which is lacking in people with Friedreich’s ataxia. A phase 1 trial completed last year in people with Friedreich’s ataxia produced promising results.

• French researchers have shown in experiments in mice that gene therapy may be a viable treatment for Friedreich’s ataxia. The gene therapy using a virus to deliver a healthy copy of the frataxin gene was able to completely reverse the heart disease (cardiomyopathy) in these mice.

New Fact Sheets now available
This year ten new factsheets have been added to the MDA website. As well as the usual description of the disorder and its cause, we aim to include the latest information on what can be done to manage the symptoms and an overview of the research into new treatments that is happening around the world. Click on the links below to view the factsheets (a printable pdf version is available for download at the bottom of each page):
Bethlem myopathy
Centronuclear and myotubular myopathy
Charcot-Marie-Tooth disease
Inclusion body myositis
Limb girdle muscular dystrophy
• Merosin – deficient congenital muscular dystrophy (MDC1A)
• Minicore myopathy
Mitochondrial myopathy
Oculopharyngeal muscular dystrophy (OPMD)
Ullrich congenital muscular dystrophy

Keeping up-to-date
• All research news updates are listed on the MDA website
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If you have any questions, or if your condition is not mentioned here and you would like an update, please contact us:

Phone: +61 3 9320 9555

Updated 3 July 2018