The 12th International Congress of the World Muscle Society (WMS), was held in Giardini Naxos in Sicily from 17 to 20 October.

 

As a member of the WMS programme committee, were you fully satisfied with the congress, in terms of the organisation or scientifically?
I wouldn’t say that I was 100% satisfied but that’s related to my character. On the whole, the congress went very well, especially given the number of participants. There was a particular problem during the poster session, which was inconvenienced by the excessive number of both people and posters. Next year, we will improve or at least change the way posters are presented. This is part of the various changes that we would like to implement next year so that the WMS congress regains its more intimate character and thereby stimulates collaboration.

 

And concerning the plenary sessions?
I was very pleased with the plenary sessions. It must be said that the programme committee selects the speakers not only on the scientific quality of their work but also on their capacity to present and their ability to transmit their knowledge. A good oral presentation is stimulating for discussions. This provides an additional quality to the congress.

 

This year, three groups of pathologies were in the spotlight: metabolic myopathies, congenital muscular dystrophies and congenital myopathies. How does the programme committee choose these topics?
Two years before the congress, we meet for one day to decide on the three themes. What we especially aim to do is highlight the diseases with novel data and therapeutic developments, obviously paying attention to topics that were previously selected. The local organizing committee may propose one or more themes, but this is subject to a very important discussion. For this year, the Italians proposed the metabolic myopathies. Initially, we were hesitant because they are complex pathologies with few laboratories working on the subject. Finally, we challenged them to find a lot of new information and we were very pleased with the results.

 

Precisely, what have you retained concerning the metabolic myopathies?
The first day that was devoted to metabolic myopathies was very rich and filled with new information. Knowledge about mitochondrial myopathies has developed enormously. Many genes are involved and the clinical presentations vary widely. I think that mitochondrial myopathy should be considered when confronted with all clinical manifestations affecting muscle, the peripheral and central nervous systems. As the diagnostic process is very complex, mitochondriopathies are extremely under-diagnosed. This is a shame because these are diseases that are sometimes treatable. A good example of a successful end-to-end diagnosis is the new metabolic myopathy presented by H. Topalogu (Turkey). It’s a complete story that starts from the clinical description of a family to the molecular diagnosis and treatment of patients.

 

What have you retained concerning congenital muscular dystrophies (CMD)?
As mentioned during my presentation at the congress, many potential treatments are beginning to emerge for different forms of CMD, although the concepts are quite complex. I am thinking particularly of the potential of a mini-agrin in merosin-negative CMD (CMD1A or merosinopathy).  We are planning to collaborate with Markus Rüegg and the company Santhera, concerning this subject. The aim is to test the AAV-mini-agrin in the dy/dy mouse model, postnatally as well as on muscle cell lines from patients suffering from CMD1A. Another collaboration that I am very happy about is the one that Susana Quiyano-Roy developed with laboratories in other countries, in particular, the USA and England. She described a new form of CMD with selective axial muscle weakness and gradual evolution, linked to mutations in LMNA. It is rare that mutations in lamin lead to such severe phenotypes, and this also raises questions about the pathophysiological mechanisms. Given the link between chromatin and lamin, severe phenotypes could reflect a deregulation of several genes involved in development. To be followed…

 

You also referred to a new form of CMD linked to nesprin. Can you tell us more?
Since these results are not yet published, we can not say too much about them. This is a new disease, probably quite rare. The involvement of nesprin (or enaptin), a protein of the nuclear envelope, is very interesting. This suggests an increasingly important role of the nuclear membrane complex. I am certain that in the next few years we will discover other diseases associated with these proteins.

 

What have you retained concerning congenital myopathies?
I particularly enjoyed the presentation of Kathy North (Australia), who gave a very comprehensive update of the congenital myopathies. In addition, these cell culture films representing the ontogenesis of rods in nemalin myopathies were fascinating. Contrary to conventional histology which gives a static image of the muscle cell, these films showed us a dynamic process. The presence of actin in the nucleus suggests it may have a role in the expression of certain genes. Indeed, there is a cytoskeleton inside the nucleus that may affect the conformation of chromatin and thus gene expression, for example, during development. However, we do not yet understand why some mutations cause the formation of rods in the nucleus and others provoke the formation of rods in the cytoplasm.
The posters on congenital myopathies were also very interesting and it is increasingly clear that mutations in the same gene can cause very different pathological or clinical profiles.

The selenopathies (myopathies linked to selenoprotein N) were the subject of two presentations. What is your opinion of these myopathies?
Dr. Moghadaszadeh (USA) and Dr. Anna Ferreiro (Institute of Myology) presented two studies that were methodologically different but their results are complementary and are in line with a key role for oxidative stress in selenopathies. This is not the first time that a deregulation of oxidative stress in neuromuscular diseases has been observed. This has already been demonstrated in laminopathies and in muscular dystrophies such as FSH and Steinert myotonic dystrophy. These data open new therapeutic prospects. Moreover, a clinical trail is underway at Santhera to test the effect of idebenon (antioxidant, analogue of coenzyme Q10) on cardiac function in Duchenne muscular dystrophy patients.

 

 

What do you think of the clinical trial results presented during the final day which was dedicated to therapeutics?
There are actually several trials ongoing of which we are beginning to see the advancement, but unfortunately, the progress remains rather limited because of regulations and administrative procedures which are very strict. For example, for the gamma-sarcoglycanopathy trial, we took one year to perform the test in only 3 patients. In addition, the production of AAV in large scale also limits the acceleration towards the drug. At the same time, as a doctor, I believe that we should not rush to the clinic before carrying out all the preclinical steps necessary for the patient’s safety. For example, concerning morpholinos or 2’Omethyl phosphorothioates for the exon skipping strategy, it would be interesting to understand what happens to these molecules over time once they have entered into the cell. Since they are made so as not to be degraded, one could apprehend an accumulation of these compounds, with potentionally toxic effects. Preclinical studies in mice or cell culture do not appear to be sufficient to study this. Hence the importance of performing preclinical research in large animals.

 

Exactly, at the congress it was obvious that there are an increasing number of studies in dogs.
Yes, dogs are the best models of neuromuscular diseases for preclinical research. However, the GRMD dog (canine model of Duchenne muscular dystrophy), whose phenotype is highly variable from one dog to another, should be used with caution. In this sense, Professor Zatz’s (Brazil) presentation was very interesting and balanced. She showed us a GRMD dog that was doing very well clinically, despite the fact that dystrophin staining was negative. Moreover, it would be interesting to further investigate the biodistribution of therapeutic products (morpholinos, 2'Omethyl phosphorothioates, AAV,…) in the dog in order to better understand the transduction variability observed depending on the muscle. All of these research projects that can sometimes seem too complicated to implement will assure a minimum risk for the future patient to be treated.

 

What do you think of the trial using PTC124 in Duchenne muscular dystrophy?
In my opinion, PTC124 has a very high potential precisely because it has no undesirable side effects and given the doses used in humans, this is a very important advantage. Preliminary results of the Phase II trial are encouraging. It is important to realize that even if treatment might improve the situation of patients by 10 or 20%, this would already be a great prospect. Especially since the majority of these patients will not be presently targeted by the exon skipping method. A major international trial to ensure the effectiveness of PTC124 should now be performed. The trial is expected to be launched in December 2007. The recruitment of centres is in progress.
PTC124 also has the advantage of potentially being used in other neuromuscular diseases such as merosinopathies or collagenopathies. We have also launched a collaboration with PTC Therapeutics to test their drugs on other diseases.
Finally, it is interesting to note that the response to PTC124 was variable from one patient to another, regardless of the type of mutation. These data might allow us to discover new aspects of the function of the spliceosomal complex.

 

 

To finish off, do you think that the Institute of Myology was well represented at the 12th WMS congress?
Yes, this was the case but it is not an aim in itself. The most important thing is to develop good collaborations with other French and international groups. Working in networks will help advance research and ultimately the discovery of treatments for patients. Moreover, a congress like the WMS is a means of making young researchers loyal to Myology. Many laboratories working on a wide variety of subjects are represented, which means a great number of potential positions for them. Myology is becoming an attractive field for young researchers and this is very positive because they are the ones who represent the future of research and hope for patients.