Skipping Multiple Exons
I just got this from google alerts and am confused. I note that the authors are not Steve Wilton's group, but what do the rest of you know about this? It sounds like they are saying that skipping multiple exon's is not feasible.....
Assessment of the feasibility of exon 45-55 multiexon skipping for duchenne muscular dystrophy
The specific skipping of an exon, induced by antisense oligonucleotides (AON) during splicing, has shown tobe a promising therapeutic approach for Duchenne muscular dystrophy (DMD) patients. As different mutations require skipping of different exons, this approach is mutation dependent.
The skipping of an entire stretch of exons (e.g. exons 45 to 55) has recently been suggested as an approach applicable to larger groups of patients.
However, this multiexon skipping approach is technically challenging. The levels of intended multiexon skips are typically low and highly variable, and may be dependent on the order of intron removal.
We hypothesized that the splicing order might favor the induction of multiexon 45-55 skipping.
Methods: We here tested the feasibility of inducing multiexon 45-55 in control and patient muscle cell cultures using various AON cocktails.
Results: In all experiments, the exon 45-55 skip frequencies were minimal and comparable to those observed in untreated cells.
Conclusion: We conclude that current state of the art does not sufficiently support clinical development of multiexon skipping for DMD.
Author: Laura van Vliet, Christa L de Winter, Judith CT van Deutekom, Gert-Jan B van Ommen and Annemieke Aartsma-Rus
Credits/Source: BMC Medical Genetics 2008, 9:105
Assessment of the feasibility of exon 45-55 multiexon skipping for duchenne muscular dystrophy
The specific skipping of an exon, induced by antisense oligonucleotides (AON) during splicing, has shown tobe a promising therapeutic approach for Duchenne muscular dystrophy (DMD) patients. As different mutations require skipping of different exons, this approach is mutation dependent.
The skipping of an entire stretch of exons (e.g. exons 45 to 55) has recently been suggested as an approach applicable to larger groups of patients.
However, this multiexon skipping approach is technically challenging. The levels of intended multiexon skips are typically low and highly variable, and may be dependent on the order of intron removal.
We hypothesized that the splicing order might favor the induction of multiexon 45-55 skipping.
Methods: We here tested the feasibility of inducing multiexon 45-55 in control and patient muscle cell cultures using various AON cocktails.
Results: In all experiments, the exon 45-55 skip frequencies were minimal and comparable to those observed in untreated cells.
Conclusion: We conclude that current state of the art does not sufficiently support clinical development of multiexon skipping for DMD.
Author: Laura van Vliet, Christa L de Winter, Judith CT van Deutekom, Gert-Jan B van Ommen and Annemieke Aartsma-Rus
Credits/Source: BMC Medical Genetics 2008, 9:105
Replies to This Discussion
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Permalink Reply by Tulika on
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Hi,
My understanding is that the sure shot way to diffrentiate between BDM and DMD is through biopsy, where the dysprohine is checked my human eye.
If its no frame shift then I would first have biopsy before I would start on steroids.
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Permalink Reply by Lori Ware on
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I agree, but I SURE wouldn't do a biopsy without being with a GREAT DMD doc in the field! There are so many times that biopsy's are done unnecessarily!
Tulika said:Hi,
My understanding is that the sure shot way to diffrentiate between BDM and DMD is through biopsy, where the dysprohine is checked my human eye.
If its no frame shift then I would first have biopsy before I would start on steroids.
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Permalink Reply by Char Burke on
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Hi Lori,
I read this article too. However, I disregarded it b/c I did talk to Steve Wilton too and he told me that he can skip Will's duplications 54-57. I know he said that some where more difficult than others but that was several years ago. I think by now he has figured all this out. It's true that the more exons skipped, the less efficiently there is. But, hey, just a small amount of dystrophin will change DMD to BMD. I can handle the fact that Will may not be able to move on his own....and need to use a wheelchair. Certainly, longevity is more important than the walking part...I know there are different types of exon compounds. There is the Dutch (which is this article) and then there is the one that Dr. Wilton is working on....I believe the one Wilton and AVI is working on is more effective with cardiac muscle. I forget the name of the type of compound but it works differently than the Dutch one. So, you may want to email Steve Wilton and talk to him. Look in your PPMD book from the convention and you should be able to locate his email there. Give Seph a big hug from Will's mom. Fondly, Char
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Permalink Reply by Nadine Foley on
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Hi Lori
We will look into getting a definite diagnosis. I told my sister what you said and she said the genetist did mention Beckers but they were going with Duchenne because of his age and symptoms. Tracey (my sis) says if a muscle biopsy is needed then that is what will be done. I know as you say you are not a doc but sometimes I think we know more than they do. You know yourself any bit of hope you will grasp with both hands. We will do all we can to get a definite diagnosis and I will let you know the outcome. Thanks everyone for all your input.
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Hi Nadine,
The difference in our boys between phenotype (symptoms) and genotype (DNA mutation) varies greatly! I think there are many boys with BMD who look like DMD. Where does your nephew live? Make sure your sister knows that she can fly free to any Dr in America that she wants to go to for an accurate diagnosis. Most of the big doc's take all kinds of insurance including Medicaid, so that should not be a stumbling block. I really believe that getting an accurate diagnosis is key to keeping our boys as healthy as possible for as long as possible!
Keep us posted!!
Lori
Nadine Foley said:Hi Lori
We will look into getting a definite diagnosis. I told my sister what you said and she said the genetist did mention Beckers but they were going with Duchenne because of his age and symptoms. Tracey (my sis) says if a muscle biopsy is needed then that is what will be done. I know as you say you are not a doc but sometimes I think we know more than they do. You know yourself any bit of hope you will grasp with both hands. We will do all we can to get a definite diagnosis and I will let you know the outcome. Thanks everyone for all your input.
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Hi Lori,
We live in Ireland, there are not that many cases of it here. So this makes me wonder if the docs are just going by text book rather than actually finding out a definite diagnosis. So many docs have never even heard of this condition. We visit the docs in the capital city Dublin, that is where the DMD docs are based. Thankfully its only an hour drive away but all tests are sent to England so take about 3 months to come back. Keep you posted!!
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Can you choose who does the testing in England? Katie Bushby is very well known. I am not sure what hospital she is at, but I believe somewhere in London...I am sure others on here can tell you!!! Or you can look in the PPMD summer conference information and find her email....
Good luck!
Nadine Foley said:Hi Lori,
We live in Ireland, there are not that many cases of it here. So this makes me wonder if the docs are just going by text book rather than actually finding out a definite diagnosis. So many docs have never even heard of this condition. We visit the docs in the capital city Dublin, that is where the DMD docs are based. Thankfully its only an hour drive away but all tests are sent to England so take about 3 months to come back. Keep you posted!!
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Thanks for all your help Lori, I will do a bit of research on it.
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Permalink Reply by Karen Barnett on
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There is Dr. Francesco Muntoni at Imperial College in London. I believe he is doing the exon skipping trials in London.
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Thanks Karen, I will try to get in touch with this Dr.
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Permalink Reply by Keith Van Houten on
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Nadine, your son's case sounds similar to my son's.
He has an in-frame deletion. His clinical findings (progression for his age) are DMD, and he's being put on steroids by Cincinnati without a muscle biopsy.
A biopsy would tell you for sure if it was BMD or DMD, but if he's weak for his age like a DMD case, it doesn't really matter. Steroids are still indicated, at least according to Dr. Wong.
Good luck.
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Permalink Reply by James Poysky on
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Yup, I second what Keith said. My son supposedly has an in-frame deletion, but his phenotype is clearly Duchenne. About 10% of boys with Duchenne have an in-frame mutation, according to the only study I could track down related to this. This makes me think that using exon skipping to move from out-of-frame to in-frame is not going to do the trick for everyone. It is not a sure-fire bet that just because you are moving to in-frame that the presentation will be changed to Becker.
You can use biopsy to try to predict where they will end up, but the diagnosis of Becker vs. Duchenne includes a number of factors including how they are presenting at the moment, what their CPK is, etc. So, if they do a biopsy and there is 30% dystrophin staining but your CPK is 15,000 and you have a hard time running they are probably not going to call it Becker. Maybe "Intermediate" or "Mild Duchenne" or something. There is no standard definition yet.
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