Can someone help me clarify something regarding exon skipping?


On AVI BioPharma's website, it states that my son's specific deletion (46-52) would be helped by skipping exon 53. (


However, when I exchanged an email with Prosensa, they stated that he would need two skips, exons 45 and 53 or exons 53 and 54.


Can anyone help explain the difference?  Are they using different techniques with their skipping or maybe they still don't completely understand the impact of skipping?


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A 53 skip alone doesn't get you back in frame. 


45 & 53 or 53 & 54 is what you need.


Look at the diagram here.  If you don't follow it, let me know and I can explain.

So if my son is missing 48-52, it looks as if only skipping 53 is fine for him.  Agree, Keith?

Yes Lisa, skipping exon 53 would allow the squared right side of exon 47 to then fit with the squared left side of exon 54.


Thanks Keith.


I have seen these charts before, but I'm just confused why the AVI BioPharma link shows a skip of exon 53 would help.


Exon skipped Potentially Repairable Deletions

53 10-52, 45-52, 46-52, 47-52, 48-52, 49-52, 50-52, 52

Seems in conflict with Prosensa's (and ActionDuchenne's) websites.


Keith Van Houten said:

A 53 skip alone doesn't get you back in frame. 


45 & 53 or 53 & 54 is what you need.


Look at the diagram here.  If you don't follow it, let me know and I can explain.

Liisa - yes, I agree with Andrea.


Keith/Jill - I'm not sure.  Doesn't seem to make sense.



A few years ago I put this exact same AVI chart in front of my doc and he was baffled. We were looking at exon 17 and he stated "under no conditions would it make sense to skip only 17. this makes no sense" or something to that effect.



Several mutations would require only an exon 17 skip.  A 12 - 16 deletion, for instance.  


A single skip of exon 17 is actually the 17th most commonly needed skip.  It's the 12th most commonly needed single exon skip.





I may not remember the specifics correctly, but the gist of it was that the AVI information referenced here was not clear and other references (such as the actionduchenne chart) were much better.

Not sure if it's a coincidence or not, but AVI BioPharma's website has been changed.  It no longer shows a skip on exon 53 being a possible correction for my son's deletion.


On one hand, I guess I'm happy this clears up the confusion.  On the other hand, this could make the wait longer for a double-skip drug...  :(


Thanks for all your help!



Given the chart link provided by Keith,  and given my son's stop codon (nonsense mutation) present in Exon 58,  exon skipping would work for him if 53-58 were skipped?  I have not found anyone yet with this exon missing.  At what point will the company start working on other skips?

AVI has been very careful not to say anything about their plans for future exon skips until trial for 51 completes. I've asked them directly on several occasions. I'm hopeful recent news from Prosensa, their main competitor, will force them to reconsider that stance, but it hasn't yet.

Generally speaking, both AVI and Prosensa refer to the exon range of 44 - 55 as the "hot zone" where the most boys can be helped, suggesting that future trials will be in this range. That seems to be what Prosensa is doing, I would expect AVI to follow suit eventually.



Donna, I don't really understand how exon skipping works with stop codons or duplications.  Send Sharon Hesterlee a note, she can explain it.  


Exon skipping in the range of 43 - 53 could probably be called a hot zone.  8 different single exon skips in that range cover 51.8% of all mutations.



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