Clinical Trials at The Center for Gene Therapy
Muscular Dystrophy Care at Nationwide Children's
OSU/Nationwide Children's Muscle Group
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Guest: Volker Straub, MD, PhD, Harold Macmillan Professor of Medicine and Professor of neuromuscular genetics at the University of Newcastle upon Tyne in the United Kingdom.
Access an abstract of this month’s featured research articles:
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 on 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. It's my great pleasure today to have as our guest, Dr. Volker Straub, who is the Harold Macmillan Chair of Medicine at the Institute of Genetic Medicine at the University of New Castle in Newcastle upon Tyne in the United Kingdom. Volker welcome
Dr. Volker Straub: Thank you very much for the kind invitation Kevin.
Kevin Flanigan: We would like to talk today about a couple of your very recent papers, both of which study magnetic resonance imaging or MRI imaging in muscle disease. And to our listeners we'll point out that links to the abstracts of these papers are available on our website. The two papers you've study here are Duchenne muscular dystrophy, which many of our listeners are familiar with and Limb-girdle muscular dystrophy type 2i.
Perhaps let's begin by telling our listeners a little bit about this disease which you call LGMD 2i.
Dr. Volker Straub: patients with Limb-girdle muscular dystrophy basically also show progressive weakness in based in all this little muscles very similar to Duchenne muscular dystrophy, and there are a number of genes that are responsible for these diseases. One major difference to duchenne is that this diseases are inherited in the so called autism recessive or dominant form which means it's not only, but always that effective, but it affects those boys and girls and there are currently about 20 known forms. We focused on the form Limb-girdle muscular dystrophy 2i because it's the most common form of Limb-girdle muscular dystrophy in the United Kingdom and in Northern Europe, but to my knowledge off in North America it's probably one of them more common forms.
Kevin Flanigan: Particularly in the UK and Northern Europe there's a common disease mutations associated with that, isn't that correct?
Dr. Volker Straub: It's very interesting for those who are looking at how mutation spread. For this common mutation in LGMD 2i is most likely originating from the Vikings, and it's the Vikings that spread the mutation when they conquered first the UK, but then went to the Normandy in France and even into the Mediterranean and you can track some of these explorations from the Vikings based on the mutations in some Italian cities.
Kevin Flanigan: Is that right? So clinically I know there's some variation in LGMD 2i but some of the patients do share a lot of similarity to Duchenne or Becker muscular dystrophy patients, don't they?
Dr. Volker Straub: When the disease was first characterize, it was actually also called severe childhood muscular dystrophy, autosomal recessive muscular dystrophy or duchenne like muscular dystrophy, so yes, I mean some of the children that are affected show a very similar type of clinical features to patients with Duchenne muscular dystrophy. This common mutation mainly affect adult patients but you have to be right that the spectrum is fairly broad and you can start to develop symptoms already before your teenage years, but the other patients it will only show first symptoms in their 30's or 40's.
Kevin Flanigan: Well let's talk for a moment about MRI, many of our listeners probably have had it done, or know some of them might have had it done, but maybe you could talk about its use, how it's used here in imaging muscle in your studies.
Dr. Volker Straub: The principle of MRI is slightly different from x-rays or computer tomography because it doesn't use any radiation. So the way images are generated is based on the water content of different tissues, and the different water content, for example between muscle tissue and the surrounding head tissue will give you different contrast in the image.
For there are, therefore no side effect. It's very safe as long as you don't have any metal object like pacemaker because in MRI is basically a big magnet that you're lying in. It makes quite a lot of noise and for boys or for children it can be bit more difficult to lay still during the examination because it's one of the requirements, and therefore we normally don't apply MRI in children younger than around six years of age.
Kevin Flanigan: But after that they can tell tolerate it pretty well, can't they?
Dr. Volker Straub: Yes.
Kevin Flanigan: Based on the table that's sort of slides into this big donut shape magnet, legs first I guess and when we're looking at leg muscles.
Dr. Volker Straub: Yes, that's absolutely right. I mean you can do this even in younger children, but if for research purposes, and then you don't want to have any seizure or sedation. And yes, you just looking at muscle diseases in most cases at the legs but it's still possible nowadays to hold body MRI that would include all your muscle, from your tongue and neck muscles down to your toes.
Kevin Flanigan: Now your studies really explore MRI imaging as a way to measure progression in muscle diseases. Why do we need a new ways to measure progression? What's important about that?
Dr. Volker Straub: There are various applications for MRI. On one hand it gives you good idea about which muscles are affected and interestingly if you look at, for example leg muscle of a patient with muscular dystrophy whether Duchenne or Limb-girdle muscular dystrophy, it's not all muscles that are affected, but some of them like... and we don't fully understand why. So you can look at the selective pattern of involvement, you can look at the extent of changes in pathology. And what we were particularly interested in you can also measure the pathology for how much muscle is still working functionally, and how much of the muscle tissue has, particular in the muscular dystrophies, been replaced by fat tissue that become quantified.
Kevin Flanigan: That's part of the disease progression for these muscular dystrophy disease that gradually muscle fibers are lost and fat replaces it.
Dr. Volker Straub: We knew already from muscle biopsies in patients that had more advance stage of disease that some biopsies contain a lot of fats that so muscle is replaced by fat. MRI can actually be very useful to guide muscle biopsies as well because it will tell you which muscle would be the best muscle to biopsy. And by coming back to your first question, so what we feel would be very interesting is to measure the progression overtime and we ask, is it necessary to have another measure? Well, one of big advantages of MRI is that it is objective, it doesn't depend on the motivation of a patient. If you look for example at the six minutes walking distance, this is something where a seven year old boy on one day might be more motivated than on another and all of us have good days and bad days where as in an MRI machine there is nothing like a good day or bad day it's a very objective measure of the muscle.
Kevin Flanigan: And for those listeners who haven't done the six minutes' walk distance even the testing that's done in the clinic with someone testing strength of the individual muscle group that requires motivation from a patient to do as well, absolutely, this takes that out. What can you measure in MRI of muscle, and what did you measure in your studies here? Imaging fat, what else do you do?
Dr. Volker Straub: So I did mention that MRI is mainly a method that looks at different water content, so you can therefor separate fat from muscle. You can also look at inflammation or edema, something that we often see in muscle dystrophy and that goes a long with an increase in water and you can also now try to look at the fibers, how they tract within a muscle that's called diffusion tensor imaging.
So there are various method, it's important to understand that the MRI, the magnet is just a machine, a tool and you can apply it in various ways depending on the question that you're asking.
Kevin Flanigan: You can do muscle volume as well?
Dr. Volker Straub: Yes, you can measure how big certain muscles are and you can also, for example inject contrast agent and see whether they show you that a muscle is more inflamed than another one. You can particularly do this at various time points so that you can see how these measures change overtime and that's something that we were interested in our Limb-girdle study.
Kevin Flanigan: So let's talk about your Limb-girdle study a bit in more detail. You have a 37 patients in this, is that right?
Dr. Volker Straub: We have 34 patients what's very important for us is that MRI has been used for many years already and there were very good publications but what was difficult is to look at MRI studies that are carried out in several centers. We have to make sure that each center is going to measure or is using the same method and is going to measure fat on muscle in the same way in we therefore look in which centers were equipped in a way that they could do this and it was our colleagues in Paris at the Institute of Neurology and in Copenhagen with John Fiche the principal investigator, and in London with Mike Hannah at Queens Square and then we, in New Castle.
First of all we make sure that we are able to measure the exact same things, and we have test runs and quality assessment for this, and we also make sure that patients were assessed by the physiotherapist in exactly the same way so they were all trained.
Kevin Flanigan: So that's for functional testing and strength testing and so forth.
Dr. Volker Straub: Yes, because we were interested to see how to the images and the pathology that we detect by MRI co-relate to the physical measures, the function or the patients as well, so 34 patients were scanned.
Kevin Flanigan: Can I just add one thing? It's important they all have the Viking mutation right? They're all the same.
Dr. Volker Straub: So thought they were all Vikings but you're right, they all have the same mutation so we wanted to make sure that we have a fairly homogeneous population at least from the underline genotype underlying genetic change. So all of them had the so called common LGMD 2i mutation in the gene that was, as we said before originating from the Vikings. Yes, they all have the same mutations.
Kevin Flanigan: Same genetic background. And what did you find in the population?
Dr. Volker Straub: quite interestingly, over 12 months period when the patients were assess by the physiotherapist and they were assessed three times, so at the beginning and then after six months and then after 12 months, we couldn't find any of our outcome measures.
Looking at strength or function that did significantly change over the 12 months period, now as a clinician you knew that these patients were getting worse and if you would have ask the patient well after 12 months how do you feel today compared to 12 months ago? Most patients would tell you, "Well I'm weaker" but as I said it wasn't possible for us and for our few therapist to really prove this by their assessment method. looking at MRI on the other hand we could tell that yes, the clinician and particularly the patients were right that there was clear progression because we could measure an increase in particularly fat in certain muscles over the same period. So some muscles show 50% more fat.
So this didn't necessarily, directly translate into a worsening of function, but clearly it was a measurable change, and measurable progression. So therefore we would now suggest or maybe to monitor any therapeutic efficacy. It will be important or helpful to also apply muscle MRI.
Kevin Flanigan: So when you say monitoring therapeutic efficacy it means for example in future clinical trials that this might be a better outcome for trials.
Dr. Volker Straub: I mean one purpose of this study was actually to prepare this patient cohort clinical trials to learn more about the natural history of the disease and the physical assessment were never the less very important and in a few single patients you could also measure that there was a worsening over the 12 months period but looking at the entire cohort, the 34 we didn't find any outcome measure that was significantly different in this 12 months period.
But yes, there would be a clinical trial looking at some therapeutic intervention than MRI for this disease but also for Duchenne muscular dystrophy is probably something that we should study more and consider in the future. Particularly I think we have to also have to keep in mind that we will see a lot of variation between patients when it comes to small cohorts. SO if you don't have the luxury to recruit your patient from a large call which we in neuro muscular diseases struggle with any way, but when it for example in Duchenne muscular dystrophy comes to smaller cohorts when you act on... type therapy.
Again, you know already that they will show a lot of variation in their strength and functions, whereas in MRI you can focus on certain muscles and be objective about it.
Kevin Flanigan: So what's next for your group then in pursuing this line of work?
Dr. Volker Straub: With the study that we have done among the four centers, we have learned and develop protocols for quantitative muscle MRI and we have published those and these protocols have now been adopted by companies as well, and they including laws into their clinical trials particularly in Duchenne muscular dystrophy. This is something that we're encouraging and although MRI will currently only be an exploratory outcome measure because we still need to make sure that is a clinical benefit that the patient can also feel. I think that for the future MRI in imaging will become more important than clinical trials.
Kevin Flanigan: And who supported this work?
Dr. Volker Straub: Thank you for bringing this up Kevin. The Duchenne muscular dystrophy research was funded by the muscular dystrophy campaign in the UK. Most of the Limb-girdle muscular dystrophy research was funded by either patient in relations in the countries like in Denmark, by the AFM in France, and by the MIC center for neuro muscular diseases in the UK.
Kevin Flanigan: Well thank you very much for explaining your work to us today and for sharing your thoughts and where things are heading.
Dr. Volker Straub: Thank you very much Kevin.
Kevin Flanigan: This Podcast is brought to you by Nationwide Children's Hospital. You can find out more about the muscular dystrophy program, an on-going clinical trials at Nationwide Children at our website nationwidechildrens.org/muscular-dystrophy-podcast. You'll also find a link to the abstracts of Dr. Straub's recent papers, and in fact a link to one of the papers in its entirety which is publicly available could be found there. Thank you for joining us.