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 Nadine Foley on
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Hi guys
If the trialserve predictor states exon skipping is not needed to restore the frame in certain deletions, and it turns out a child has DMD, will exon skipping still work for these deletions in changing the child's DMD to BMD??
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Permalink Reply by Keith Van Houten on
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Rhiannon - who did you ask - a neurologist, or a gene researcher? Just wondering.
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Permalink Reply by carrie on
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Rhiannon Hubbard said:Keith, we asked both. Our local Neurologist (who says he asked Dr. Flanigan about the subject) and then most recently the genetics Dr. from UCI.
whats his mutation?
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Does anyone know what future therapies will help these 10% of boys???
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Permalink Reply by Lori Ware on
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While exon skipping will help boys out of frame, it will only take them to a Beckers. So, my son is out of frame and can be helped by exon skipping, but I am looking forward to Utrophin Upregulation.
Nadine Foley said:Does anyone know what future therapies will help these 10% of boys???
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Permalink Reply by djamel fathi on
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Roxanne Roberts said:my son's deletion is in-frame 45-47. I'm also very excited about Utrophin Upregulation. Since Utrophin is in the body in low amounts I don't think there will be any problems with attacks from our boys immune systems. This excits me!
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Hi,what mean deletion of exons[in frame] &[out frame]?
my son's result is deletion of exon 45 only.nothing else was in his result .
I'm still waiting for a soonest appointment with Dr FENKEL at chophiladelphia,to answer a lotof question I didn't get from our first neurologist or at least she never mention in frame or out....
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When we talk about in-frame or out-of-frame deletions, we're talking about how the mutation has disrupted the dna sequence. This is a complicated subject, and I'm by no means an expert.
To oversimplfy things, you can think of the DNA as a string of 3 letter words.
THE CAT ATE THE RAT
The DNA is "read" as cells are created in sequences of three. An out of frame deletion would disrupt the reading sequence. For example, if the deletion took out the T from CAT. The DNA would be read like this:
THE CAA TET HER AT
The result is a totally jumbled sequence, and the "recipe" for making the protein is lost.
By contrast, an in frame deletion takes out part of the DNA sequence such that it still makes "some" sense. For example, if the deletion took out ATE, you'd get
THE CAT THE RAT.
Here, there's still some resemblence to the original intent. You would get some type of protein created, although it might not be quite correct, or you might not get as much.
This general concept is referred to as the "reading frame rule". You can google it and find more, and better, explanations than this.
An exon 45 deletion is out of frame. There's a predictor to determine that at this website: http://www.dmdregistry.org/reports/predictor/
Good luck.
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Hi,you said an exon 45 deletion is out of frame,but what I have in the result , my son have an in frame shift,wich is consistent with dmd. is that different from what you saying or what? I appreciate your answer.
Keith said:When we talk about in-frame or out-of-frame deletions, we're talking about how the mutation has disrupted the dna sequence. This is a complicated subject, and I'm by no means an expert.
To oversimplfy things, you can think of the DNA as a string of 3 letter words.
THE CAT ATE THE RAT
The DNA is "read" as cells are created in sequences of three. An out of frame deletion would disrupt the reading sequence. For example, if the deletion took out the T from CAT. The DNA would be read like this:
THE CAA TET HER AT
The result is a totally jumbled sequence, and the "recipe" for making the protein is lost.
By contrast, an in frame deletion takes out part of the DNA sequence such that it still makes "some" sense. For example, if the deletion took out ATE, you'd get
THE CAT THE RAT.
Here, there's still some resemblence to the original intent. You would get some type of protein created, although it might not be quite correct, or you might not get as much.
This general concept is referred to as the "reading frame rule". You can google it and find more, and better, explanations than this.
An exon 45 deletion is out of frame. There's a predictor to determine that at this website: http://www.dmdregistry.org/reports/predictor/
Good luck.
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Hi Lori
I looked up my newphew's deletions on the leiden trial serve and it says ....deletion exon 4-18 leads to ..an IN-FRAME deletion. I know exon skipping will only fix out of frame deletions and will not work for in-frame deletions. We are still waiting to hear from the doc for a way for get Travis a definite diagnosis not just based on age & symptoms. But we are 99% sure it is DMD, that last 1% is just the hope left in us.
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Hi Lori
The genetic doctor phoned and Travis has a CK Level of 20,000. So with this, his age and his symptoms they have given a definite diagnosis of DMD. They will put it in writing and send it to my sister. Thanks for all the information :-)
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djamel fathi said:Hi,you said an exon 45 deletion is out of frame,but what I have in the result , my son have an in frame shift,wich is consistent with dmd. is that different from what you saying or what? I appreciate your answer.
I think you're mixing up some of the terms. This is understandable, this is a complicated subject, it takes time to soak this all in.
You said "what you have in the result". You mean from the doctor, or from the trialserve predictor? Here's what you should get from trialserve for an exon 45 deletion:
The Large Deletion starts in Intron 45 and ends in Intron 45.
The variant caused a frameshift of -2 nucleotide/s.
An OUT OF frame UGA (Opal) stop codon was predicted, in exon 46.
So, it's an out of frame deletion. When you see the term "frameshift", what they're basically talking about is whether the reading frame is disrupted. An out of frame deletion results in a frameshift.
In the majority of cases, an out of frame deletion is associated with DMD. An in frame deletion is associated with BMD. There are exceptions, though. It's a rule of thumb.
If you have a different result from a doctor, go with that. This trialserve tool is only a predictor, from what I understand.
Again, take my information - and for that matter anybody's that you get on this board, or anywhere else on the internet, with a grain of salt.
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