Clinical Trials at The Center for Gene Therapy
Muscular Dystrophy Care at Nationwide Children's
OSU/Nationwide Children's Muscle Group
Podcast: Click here to Download
Guest: Professor Francesco Muntoni, Chair of Paediatric Neurology, United College London Institute of Child Health, Dubowitz Neuromuscular Centre
Access an abstract of this month’s featured research article: The ever-expanding spectrum of congenital muscular dystrophies. Ann Neurol. 2012 Jul;72(1):9-17.
Dr. Kevin Flanigan: Welcome to This Month in Muscular Dystrophy. I'm Kevin Flanigan from the Center for Gene Therapy at Nationwide Children's Hospital in Columbus, Ohio.
Each month in this podcast, we invite authors of recent publications to discuss how their work improves our understanding of inherited neuromuscular diseases and what their work might mean for treatment of these diseases.
Today, it's my great pleasure to have as our guest, Dr. Francesco Muntoni. Dr. Muntoni is Professor of Pediatric Neurology, Director of the Dubowitz Neuromuscular Centre and Co-Director of the MRC Neuromuscular Disease Center at University of College of London and Great Ormond Street Hospital for Children in London. Francesco, welcome.
Dr. Francesco Muntoni: Good morning.
Dr. Kevin Flanigan: Thanks for being with us today.
Dr. Francesco Muntoni: And thank you for asking me to come here.
Dr. Kevin Flanigan: We're going to discuss and we have a link on our webpage to a very terrific review that you just published in Annals of Neurology called the Ever Expanding Spectrum of Congenital Muscular Dystrophies.
Maybe we could start with the term congenital muscular dystrophy. What does that mean in comparison to other muscular dystrophies?
Dr. Francesco Muntoni: So the term implies at much earlier onset of presentation for these children. Often, these children already have problems at birth and congenital means that already some damage to the muscle has occurred before the children are born. And clinically, they will present either immediately at birth or in the first few weeks or months of life when delay in the motor milestone becomes apparent in these children.
So this is in fact very different from a group of more well-known childhood or adult onset muscular dystrophy or the limb-girdle muscular dystrophy where in the first few years of life, the muscle doesn't already have sufficient damage to cause trouble.
Dr. Kevin Flanigan: So this is to suggest these are problems in the development of muscle or embryonic development or what does that tell us about this?
Dr. Francesco Muntoni: As you are indicating, the pathogenesis must be quite different compared to those conditions which progressive damage starts to occur and accumulate after birth. In this condition, before birth – already at birth actually, the muscle vibes, you have children with many of these congenital muscular dystrophy will show very advanced stages suggesting that the timing of the pathology has occurred in utero and therefore, suggesting that several of the pathogenetic mechanism that make damage to muscle, let's say in limb-girdle muscular dystrophy that is mechanical loading to some extent and usage, are probably not so much relevant in this group of condition. In congenital muscular dystrophy therefore, although the process is still being illustrated, this evidence that the way their muscle form and in particular, satellite cells proliferate and expand is affected.
Dr. Kevin Flanigan: Satellite cells, for some of our listeners who might not know, are specialized cell in muscle tissue that help replenish and generate muscle tissue.
Dr. Francesco Muntoni: There you say it, yes.
Dr. Kevin Flanigan: There are a wide variety of congenital muscular dystrophies with a wide range of assorted clinical features. Can you tell us a little bit about the range of these syndromes?
Dr. Francesco Muntoni: In fact, there are genetically and these a very heterogeneous group of condition. Say, up to 20 years ago, there appear to be only two sub-types. One sub-type with brain involvement that was, if you like the Japanese sub-type of Fukuyama muscular dystrophy. And then was all the rest without severe brain involvement. And up to 20 years ago, you would have the Fukuyama, the known Fukuyama type of congenital muscular dystrophy.
The field has now certainly exploded in terms of the understanding of the heterogeneity of this group of condition and also in appreciation of if you like, the various sub-type with or without brain involvement. We have essentially a condition that range from the most severe end of the spectrum as in Walker-Warburg syndrome. These are a condition where children are born not only with a very severe form of muscular dystrophy, but also have extremely severe brain and eye structural malformation
And if anything, it is the structural malformation that determines how severe the condition is and usually, the inability of these children to survive long. They are then at the other end of the spectrum. There are conditions in which the brain is certainly not affected at all, and in which the severity is compatible with, for example, the ability to learn to walk or maybe a little late and with the ability to maintain, for example, the ability to walk for several years.
Although in general, in the majority of the syndromes although not in all, disability will be lost at some point.
Dr. Kevin Flanigan: So that's a quite a broad, broad range then.
Dr. Francesco Muntoni: It is very broad range.
Dr. Kevin Flanigan: So we'll keep that in mind as we sort of discuss genetic causes and advances in it and so on. Well, given this variety, then how do you classify in modern times, you mentioned 20 years ago, how do we classify this now?
Dr. Francesco Muntoni: So what has been very fascinating in the last 15 years is to see that the group of proteins that gives rise to congenital muscular dystrophies, they are not randomly distributed in the proteins that are present in muscle but they appear to be clustered in a group of proteins that have similar location and most likely, similar function.
And this group of proteins, on the whole, is quite different from the group of proteins that give rise to say, forms of exclusively late onset such as some of the limb-girdle muscular dystrophies and so on.
So what has been clear is that extracellular matrix proteins meaning proteins that are expressed just outside the fibers and connect the fibers to the say the glucose that is in between the various muscle fibers. It is clear that proteins in that location play a significant role in a congenital muscular dystrophy. There are multiple examples of several proteins in that area that are, when affected, give rise to congenital muscular dystrophy. There is then and they represent the most common groups.
There are then another exciting and again, in very rapid evolution field, what we are finding is that there are another group of proteins called enzymes. These enzymes are involved in modification of proteins that are already present mostly in the extracellular matrix.
And therefore, you actually have that most of what is happening in this condition is perturbation either of proteins present in their extracellular matrix because mutation affects those proteins primarily or affects the way these proteins that are outside the muscle fibers are assembled because there are enzymes that control the fine tuning of how this protein should be assembled that goes wrong.
Dr. Kevin Flanigan: So there's sort of linkage between the muscle membrane and this matrix you described.
Dr. Francesco Muntoni: In a way or the other, that is the common link between the majority of this condition. There are some exception in all fairness, there are some rare forms of congenital muscular dystrophy that have completely different mechanism. But what we just described probably takes care for 90% of all congenital muscular dystrophy and then there will be some exceptions.
We do not understand yet exactly what goes wrong in those exceptions although there is evidence, for example, in rigid spine syndrome and cellular protein deficiency that holds in that group of condition. There is quite a severe dysfunction of the way the satellite cell, meaning this muscle precursor and stem cell that allow muscle to be formed properly and to regenerate properly. They are quite significantly affected.
Dr. Kevin Flanigan: That is why.
Dr. Francesco Muntoni: That's right. Maybe that with this mechanism all affected the way the muscle is formed.
Dr. Kevin Flanigan: A listener is interested in that last script. In particular, Dr. Allamand was on this podcast a few months back talking specifically about selenoprotein and satellite cells. Let's go back a moment to your two major categories that account for about 90%. You said one group of those, I know, you termed it dystroglycanopathies. Maybe you could just talk about those as a group, what they share in common and what we sort of think what we know about and what we've learned about them.
Dr. Francesco Muntoni: Yes. So this is again is something that if you look into your problem at into the internet and look for this group of condition up to let's say, 11 years ago, you will find nothing. And this now are one of the most intriguing and common form of muscular dystrophy that exists. There is a pivotal molecule called dystroglycan.
Dystroglycan has got two sub-units. One of the sub-units is in the external part of the membrane and connects extracellular matrix proteins that we were describing before. And this connection is mediated by a contact with these extracellular matrix proteins that is for which a particular type of glucose that are sugars is necessary. So dystroglycan link to for example, protein such as laminin, that is a very important protein of the extracellular matrix.
Just because there is a particular coating on dystroglycan, that in this coating are a multiple types of sugars.
Dr. Kevin Flanigan: And there's a process glycosylation recall.
Dr. Francesco Muntoni: This is process is the glycosylation of dystroglycan and what we have learned by this understanding this is this process is that there is not a simple sugar. So the glycosylation steps is not just one, there are multiple, very complicated glycosylation steps that add different type of sugars and therefore, different type of glucose, let's say, outside the dystroglycan. And until let's say, the beginning of this year, we had seven examples of mutation in enzymes that each facilitate this sugar deposition.
Dr. Kevin Flanigan: So just a reminder to our listeners, enzymes are proteins that do some activity. It do some work in the cell and these enzymes are each added as step of the sugar process, the glycosylation process.
Dr. Francesco Muntoni: That's right, exactly. So until very recently, we had examples of mutation in seven of these proteins that facilitated the deposition of sugars on dystroglycan. And therefore seven types of dystroglycanophaties.
But much more recently and this is this year, thanks to the advent of next generation sequencing and so there has been an explosion of identification, another genes responsible for dystroglycanopathy.
Dr. Kevin Flanigan: So the next-generation sequencing is all the new tools that we have available that people read in the newspapers about advances in genetics or genetic technology is easier. Some of those technologies, right, that allows us to look at many genes at one time.
Dr. Francesco Muntoni: That's right.
Dr. Kevin Flanigan: To help this gene discovery.
Dr. Francesco Muntoni: And it helps also because it allows relatively small families. You don't necessarily need it, they're all techniques that require that you had relatively large families to try to understand what was shared between multiple affected individuals in the same families. But with this next-generation sequencing, in theory, a single family, a singularly affected child can provide a clue to tell what is the gene involved. And certainly, four more genes had just been identified the last few months for this group of condition and two were identified by us in a single tone, meaning a single affected child in a single family gives you a clue and then you expand, of course, to screen a larger part of your core of individuals with this type of condition.
And I'm fully aware that others are also working on this and probably, there are two more genes being fund as well. So within six months, it's like almost doubled the number of genes responsible for this group of condition.
Dr. Kevin Flanigan: And they all work through the same general pathway of adding sugars to the dystroglycan to improve the linkage to the extracellular matrix.
Dr. Francesco Muntoni: So many of these genes, what exactly or how exactly they put to these sugars on dystroglycan, we do not know. We know the end product that dystroglycan appears to have very little sugars and therefore cannot connect properly to the extracellular matrix.
Dr. Kevin Flanigan: Now one thing your own work has shown, I know and you mentioned in the paper that many of this individual instance, we now associate a wide and overlapping range of clinical illness that is a mutation in one of these enzyme steps. Looks very similar to mutation in another enzyme step and that whole range from most severe to less severe is represented in each of these. Is that correct?
Dr. Francesco Muntoni: Yes, you're absolutely right. So in a way, if you go back to what we were describing as the mechanism of disease being the effect on coupling or the poorer linkage of dystroglycan to proteins of the extracellular matrix and laminin in particular, but others as well.
If that is the mechanism, then what is the enzyme or what is the protein that affects, this process doesn't matter that much because the end product is like saying, you can have your tire flat by a number of different means but at the end of the day, the tire is flat.
Dr. Kevin Flanigan: Is that commonality then give you a hand along therapy? Does it help think about therapy for this?
Dr. Francesco Muntoni: Well, I think this commonality is important for a variety of reasons. The first is that from a diagnostic perspective, it is a complication because you could have that one – well, you have that a single event meaning on biopsy, you look at the biopsy of a child and this child has reduced dystroglycan. Glycosylation is not at your – then cannot just chase a single condition. You need to chase multiple conditions.
And as we just described, the number of conditions is expanding very rapidly and I will not be surprised that in a few years time, we would have maybe 20 or more dystroglycanopathy.
So from a diagnostic perspective, this complicates things and for listeners, it's important to realize that this is a moving target. There are still many families without a final diagnosis.
Dr. Kevin Flanigan: So that I was just going to mention it for listeners who might have a child that's still been undiagnosed until a year ago. You might say it's a reason to make sure you return to clinic and be re-evaluated regularly because there are new tools available to help out with that.
Dr. Francesco Muntoni: That's entirely right. Again, certainly in our clinic, they will be truly not tested for these genes that are just going to be published now and therefore, is a process that needs to be updated. But it's still possible then at the moment that there is not single gene that will be responsible for one particular child so it's not possible to diagnose every single child at the moment.
You alluded to the other point that relates to the fact on where this information can be – the information that dystroglycan and the extracellular matrix are not linked properly could be exploited therapeutically. And there is work that is being done across multiple continents, in this country, there is work done in Japan, there is work done in Europe by our group and group of others.
That suggests that it is possible at least theoretically, so I'm not suggesting this is today a cure you can get in the pharmacy. But it's possible to increase the amount of sugars on dystroglycan by some like tricks. And these tricks are over-expressing in an artificial way some of the enzymes that we know that put sugars in dystroglycan.
So we can, for example, by gene therapy or other genetic modification makes some of these enzymes work extra time, if you like. And these extra times worked puts extra sugar on dystroglycan and even in children when in cells of children or of models, animal models that are missing individual's enzymatic step.
And the proof that this work in for example, animal model, is at the moment, incomplete. There is work that has been performed in several places to tell exactly how much this upregulation would be able to improve the severe type of some of these models. And if that was the case, if this was proven, this would be quite interesting for a variety of reason.
Firstly, it is anticipated that some of these therapies might work across several conditions, meaning it would not necessarily or theoretically, this still is to be proven, will not necessarily work for a single condition where there is a problem of a particular gene but every time or in most instances where dystroglycan doesn't have sufficient sugar, this could be effective.
The second reason why this would be of interest is that work that has been done by us and by the group of Kevin Campbell here in the States suggest that the amount of sugars that you will need to put again on dystroglycan to improve the linkage with the extracellular matrix is relatively modest. And therefore, it is theoretically feasible to start thinking about upregulation of these enzymes that put this sugar on dystroglycan by what we call small molecules, so by pharmacological upregulation as opposed to gene therapy that in a way, might be most likely less effective than gene therapy pharmacological upregulation just by drug.
But at the same time will probably be sufficient to at least start to see an effect and probably applicable to young adult individuals where the path for developing gene therapy may probably be a bit longer.
Dr. Kevin Flanigan: A bit more challenging in some ways, right? Well, back to the clinical features for a moment. I know this quite a wide variety of some nerves as you pointed out, are there any general or common pieces of advice that you give to parents or pediatricians of patients with congenital muscular dystrophies? That's a big question, I know, but I...
Dr. Francesco Muntoni: Yes, but it's actually quite easy to answer. The answer is yes. You know, if you like, we need to take advantage of the knowledge now we have of these conditions as we discuss – some of these conditions are quite severe conditions.
Having said that, many of the complication that occurs to this group of children and are very well understood, the natural history of this condition is better understood than he was just five years ago. We know what is it that cause trouble to these children especially those children who are, for example, are able to, not necessarily at this point in time that they're at the very, very severe end of the clinical spectrum such as children with Walker-Warburg for which realistically at the moment, there is no really prospect of therapeutic intervention.
But for children who make an example like medicine-deficient congenital muscular dystrophy, all rate of muscular dystrophies and many dystroglycanopathy patient in whom really what cause trouble is the respiratory insufficiency. There may be in some of these conditions, cardiac involvement.
We know when this problem will arise. And the regular follow-up in clinic with targeted intervention allows to anticipate when problem will occur in being a step ahead of the disease process. And therefore, do not allow some of the complications to occur. And this has revolutionized the care of these children and eventually, their survival.
Dr. Kevin Flanigan: And there are many clinics certainly, in the state sign of the situation better, there are certainly clinics with integrated pulmonary and cardiac care. But even if they don't have access to these clinics, they should seek out to their pediatrician the regular care of pulmonary and cardiac issues, it sounds like.
Dr. Francesco Muntoni: I think, in a way, as these are rare conditions, it would be advisable that colleagues with expertise in this group of condition, we're dealing with children affected by these forms, it doesn't need to be a world expert of each of these conditions.
But certainly, access to multidisciplinary team and focusing on the care, cardio or respiratory care means that what before, like for example, all rare congenital muscular dystrophy, laminin-alpha-2-deficients were considered to be really childhood disease with no perspective of adult life. And we now transition 95% or more of these young people to our adult colleagues. And just ten years ago, this would have been impossible.
Dr. Kevin Flanigan: Alright, well good. Well, one last question is what's your plans moving forward with this group of diseases?
Dr. Francesco Muntoni: I think what will be – there are a number of – actually there is not a single step but a number of different steps.
The first is that understanding better what goes wrong in the muscle of these children is meaning that we are able to, we meaning the community, is able to identify interventional steps better than just a few years ago.
We understand for example better, what are mechanism that leads to muscle degeneration in some of these conditions. And there is now advanced plans to perform, for example, clinical trials with drugs that intervene in some of these steps. In conditions like all rare conditional muscular dystrophy and laminin-alpha-2-deficient congenital muscular dystrophy. So that will be very exciting. It will be the first time ever that this group of children will be able to be exposed and benefit, if you like, from the clinical research and therapeutic trials. And I think this will be certainly be exciting.
A more complicated step that will be essential is to have a better understanding of what is that this values enzymes going back to where describing – discussing before, which is exactly the mechanism of glycosylating, putting sugar on dystroglycan.
And this is clearly is much more crucial process in the muscle fiber formation and maintenance that was supposed until just a few years ago and while finding these new genes is exciting, the full understanding of exactly what this gene do, the full understanding whether the target of their sugar addition is only dystroglycan or there are also other proteins, is a big challenge that the scientific community has to face and we're doing some work and many other people are doing a lot of work. And this would have very, I think, fundamental implication because dystroglycan is important for muscle. It is important for heart, it is important for brain and therefore, there are implications even outside the field of just the skeletal muscle weakness these children have that will be quite important for the field.
Dr. Kevin Flanigan: Well, thank you very much for taking the time to discuss your work with us and your perspectives on the field.
Dr. Francesco Muntoni: Thank you very much for asking me to come.
Dr. Kevin Flanigan: This podcast is brought to you by Nationwide Children's Hospital. You can find out more about the muscular dystrophy program and ongoing clinical trials at Nationwide Children's at our website, nationwidechildrens.org/muscular-dystrophy-podcast. You'll also find a link to the abstract of the recent review that we've discussed today.
Thank you for joining us.