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 Jimmy Mooney on
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I would say they are unable to skip 11 exons together but it could still be feasible to skip a smaller group.
Prof wilton has shown he can do two exons in mice i think it was 52-53 and they used a skip of 3 in the dog studies.
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Permalink Reply by MarcosDad on
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With current exon skipping technology there is a geometric decay of efficacy with multi-exon skipping. So the more exons you skip the less effective it will be. That is what I gathered from a discussion I had with Dr. Wilton a couple of years ago wrt skipping multiple exons for duplications. I guess once they start improving the targeting technology they can get better efficacy and thus if they can reach a reliable efficacy regardless of combination of targets then it would be feasible to target 2,3, or even 11 at a time and still be effective.
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Permalink Reply by djamel fathi on
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what that mean multiexon 45 55?
Is that mean kids with multiple delition in betwen exon45 and exon55?
or,WHAT???
I wish to have an answer on this,whit more details,please.
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Permalink Reply by Lori Ware on
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Djamel,
i think 45-55 is just a large group of exons that is in the most common area for deletions. If they were able to skip that set of exons then they may be able to put a lot of boys mutations back in frame. For example, my sons deletion is 46-50 so skipping 45-55 would help him even though you are skipping more exons than he needs. Basicallly this set can help the most boys at once rather than waiting on approval/development for each individual skip that may be needed.
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Permalink Reply by Jennifer on
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My son has a deletion of exon 49 and 50. I thought that skipping exon 51 would help him, was I wrong?
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you are probably right. If I recall, we have to skip 45-51 to be in frame with a deletion of 46-50.
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What is key to skipping this range of exons (45-55) is that there were OLD people found with this range of exons missing in the DMD gene! That is the resulting dystrophin protein is fully functional.
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Permalink Reply by Nadine Foley on
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My nephew has a deletion of exons 4-18, I take it exon skipping is not going to help him.
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Hi Nadine,
According to the exon skipping predictor, your nephew would not benefit from exon skipping as he does not have a frame shift deletion...most likely meaning that he already has Beckers, not duchenne (is that right?). Below is what the predictor said:
Variant Prediction - version 0.8 at Thu Dec 04 14:34:51 GMT 2008
This prediction is for illustrative purposes only and is without warranty.
Please consult your clinician about the information given.
The change in the DNA is c.187-?_2292+?del
The change in the RNA is r.ex4_ex18del
The change in the Protein is p.Pro63Asn764Aladel
The Large Deletion starts in Intron 4 and ends in Intron 18.
No frameshift was found in the prediction.
No stop codon was found either in or out of frame
Exon skipping is not needed to restore the reading frame.
Exon skipping will take boys with DMD and turn them into a Becker with a small amount of dystrophin being produced. If your nephew has been told he has DMD, not Beckers, without a frame shift in the DNA, I would speak with either another geneticist or neurologist about the diagnosis, just to clarify.
good luck!
Lori
PS...I am always subject to interpreting this stuff wrong! So, PLEASE don't take my interpretation as gospel!!!!
Nadine Foley said:My nephew has a deletion of exons 4-18, I take it exon skipping is not going to help him.
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Hi Lori, my heart just stopped there for a second, travis has been diagnosed with DMD.
No muscle biopsy the docs said that as hes only 7 and has been showing signs for a
few years now that it is DMD.
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Like I said Nadine, don't take my word for it, but according to the predictor (which I think is pretty reliable) there is no frame shift...meaning, there should be some dystrophin produced. There are boys with Beckers who LOOK like DMD, but are actually Beckers by Genetics. If I was you all, I would get to a GOOD genecist at a GOOD clinic or at least talk to one! My understanding...and I am IN NO WAY the best on here with genetics, if you are IN FRAME...NO FRAME SHIFT, then your geneotype is Beckers. I would not rush out and get a biopsy, but I would talk to someone knowledgeable. I bet even Pat Furlong at PPMD could help you with this!!! Give her a call! Good Luck!!!
Lori
Nadine Foley said:Hi Lori, my heart just stopped there for a second, travis has been diagnosed with DMD.
No muscle biopsy the docs said that as hes only 7 and has been showing signs for a
few years now that it is DMD.
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