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. (http://www.avibio.com/our-programs/rare-diseases/duchenne-muscular-...).

 

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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Donna, I can help with that -- and perhaps this will make the question easy for you to field too, Keith.  If there is a stop codon in an exon that can be skipped and leave an in-frame transcript, you just skip that exon.  If skipping the exon puts the downstream message out-of-frame, you skip a few exons until you get the downstream message in-frame.

 

Skipping exon 58 would cause a frameshift, but skipping both 58 and 59 gives an in-frame transcript. 

 

That sounds straightforward, but we still need to know what functions are located on the skipped exons -- especially when there are several possible groups of target exons that will work to get rid of the exon with the stop codon.  You'd want to chose the group of target exons that cause dystrophin to retain most of the abilities of healthy dystrophin.  This is an active area of research now.

That makes sense about the stop codon and how skipping applies.  Thanks.

 

This subject of understanding which exons produce the most effective dystrophin goes back to an earlier conversation of ours, Jon.  Rare exon skips may be the ones that produce the best dystrophin.  Prosensa's going forward with the next exon skipping drugs that have the biggest market - which makes sense from an economics standpoint, but maybe not a scientific standpoint.  My biggest fear is that if we have poor results from these first 4 drugs, the other 65% of the DMD population never gets to find out if exon skipping would have worked for them.  Best case scenario is they all work great, the drug companies are awash in cash, and they go after the rest of the market.  

 

 

I think the answer lies in a BMD database.

 

Is there any BMD database which tells how many BMD folks have what kind of in frame deletions? Having such information will also be very beneficial to the drug companies who can figure out how a wild type occurance of shortened dystrophin behaves. This wild type occurance should act as a reference point for the effectiveness of a drug that causes a in frame deletion.

 

A BMD database should also answer other questions which Keith raises;Should drug companies focus only of the population of DMD or should they also look at how effective the exon skipping science can be for DMD populations who may be very small but highly responsive to a inframe shift cause by a drug.

 

 

 



Jon Moulton said:

Donna, I can help with that -- and perhaps this will make the question easy for you to field too, Keith.  If there is a stop codon in an exon that can be skipped and leave an in-frame transcript, you just skip that exon.  If skipping the exon puts the downstream message out-of-frame, you skip a few exons until you get the downstream message in-frame.

 

Skipping exon 58 would cause a frameshift, but skipping both 58 and 59 gives an in-frame transcript. 

 

That sounds straightforward, but we still need to know what functions are located on the skipped exons -- especially when there are several possible groups of target exons that will work to get rid of the exon with the stop codon.  You'd want to chose the group of target exons that cause dystrophin to retain most of the abilities of healthy dystrophin.  This is an active area of research now.

Tulika,

 

Am not sure but there is a study attached here for BMD patients have exon deletion from 45-51. BMD patients having inframe deletion from 45-51 have survived almost like normal human beings.

 

Rgds...Anup

Attachments:

Fantastic paper, Anup.  Thanks.

 

 

 

Keith,

Am looking for same kind of research study for other BMD patients having other deleted exons. I have written to author of this document but he don't have anything more than this. My son is having a deletion of exon 49 and 50 and he will be benefitted by exon 51 skipping but that is also a long way away. I interacted with GSK and Prosensa just 2-3 days back and they are expecting a time frame of 5 years for commercial launch of exon 51 skipping. Tooooo looooong a wait.

Rgds...Anup

 

Really?? 5 years to the commercial launch of patch 51? Who did you speak to Anup? This seems a much longer time frame than expected. This is very upsetting.

"5 years for commercial launch of exon 51 skipping"

 

 Coming from the mouth of GSK I might question that time frame since AVI is making a full frontal assault on exon 51 as we speak. 

 

You might want to review this video. it has nothing to do with duchenne but there is a message in the video. Avi might fail but with ducheene but it will not be because that didn't make a full court press the last 8 months

 

http://www.youtube.com/user/russopartnersllc#p/u/4/CZNQJQ7I-ws 

I would like to understand more too.  Since my son needs multiple exons skipped, we need 51 released so the other exons can also be released.

 

And let's not kid ourselves - this is a for-profit company.  They have and will continue to invest millions of dollars into this product to make a profit.  I highly doubt they would continue into Phase III if the didn't have a very promising product.  Further, I doubt they'll wait 5 more years to start bringing in revenue.

 

Keep in mind AVI BioPharma's working on this too so there should be some competition to be the first to market...  

 

Keith

 

 

" this is a for-profit company " I totally agree but for AVII this is a do or die situation financial  wise. There not sitting on billions like GSK and the stock is trading at a buck. A lot of folks are expecting them to fail and have placed there bets that they will.

 

The CEO at AVI has made this an all or nothing bet.  I think they have the right science at the right time with the right leadership.

 

Will see soon enough.


Following is the mail which i have recd. from Prosensa Netherland just last week on 15th Sep. Am equally disturbed. I hope they will do it earlier than what is stated in mail below.

"Dear Anup,


 


It is not possible to say if and when exon 51 skipping will become commercially available.


 


Currently a phase III clinical trial is ongoing to hopefully confirm the treatment work and is safe. Only if this is the case (both safe and effective) will the exon 51 skipping compound become registered as a drug.

The trial was started in 2011 and it is anticipated that results will become available in 2012/early 2013. If these results are as we hope (safe and effective) they will have to be discussed with the regulatory authorities who in the end decide whether or not to register the drug. Of course Prosensa Therapeutics and GSK (who are developing the drug) will do everything they can do make this process as quick and as smooth as possible, but it takes time. As we are not always in control of what will happen when (e.g. recruitment of patients takes time, discussion by authorities takes time, we hope the drug is safe and effective, but this is currently tested) it is not possible to make any predictions. If all works out well it should be within 5 years, but if things do not go as planned it can take longer or if exon 51 skipping turns out not to be safe or effective, it will never become available...


 


For more information on exon 51 skipping development, please look at


 


Best regards

Annemieke


 

 


Annemieke Aartsma-Rus

DMD Genetic Therapy Group

Department of Human Genetics

Leiden University Medical Center


 


Email:


 


Adress

LUMC Postzone S4-P

PO Box 9600

2300 RC Leiden

The Netherlands

tel +31 715269436

fax +31 71 5268285"


Sent: 15 September 2011 07:30
To:
Aartsma-Rus, A.M. (HG)
Subject:
parents/patients website question

 

www.dmd.nl/gta.m.rus@lumc.nlwww.prosensa.eu

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