Hello,

My boy got Stop Codon Mutation - Exon 16 (p.K632X). Any boy have same mutation ? Need yr advise.

Much thanks.

Trinh

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Trinh, I have the same mutation as your son. Although I don't think I can be of much help, I'm sorry.  But if it makes you feel better, I'm almost 20 and in my second year at University and can still do all of my assignments without assistance.

Dear Maria,

I am so emotional when receiving yr message. It is great that you are 20 and in 2nd year at University. The news is really supportive.  Allow me to know more about you. Can I contact you by e-mail ? My address is : trinh_nguyen@nst-vn.com.vn

Take care.

Trinh

Maria Salamon said:

Trinh, I have the same mutation as your son. Although I don't think I can be of much help, I'm sorry.  But if it makes you feel better, I'm almost 20 and in my second year at University and can still do all of my assignments without assistance.
Sure, my email address is salamon.2@wright.edu

Trinh Nguyen said:

Dear Maria,

I am so emotional when receiving yr message. It is great that you are 20 and in 2nd year at University. The news is really supportive.  Allow me to know more about you. Can I contact you by e-mail ? My address is : trinh_nguyen@nst-vn.com.vn

Take care.

Trinh

Hello Jon,

 

First of all thank you so much for explaining exon skipping so well, and thanks a lot also for the link to that chart.

My son has a nonsense, stop codon mutation in exon 7, so I understand he would need to skip exons 6, 7 and 8.

Anybody knows if either Prosensa or AVI Biopharma are looking into this particular set of multiple exon skipping? .

In my family we were extremely hopeful about Ataluren (PTC-124), and we still cannot believe that they almost threw almost ten years of clinical trials down the drain because the boys on low-dose Ataluren fell short of the expected outcome by a margin of ONE PERCENT in the 6 minute walk test. Fortunately they re-started the trials but only for those boys who were already enrolled, and it all looks quite ridiculous, so now we are hoping that exon skipping may go ahead.

Best wishes

Bernardo  

Good day Bernardo,

 

I agree - since your son is already skipping exon 7, oligos targeting exons 6 and 8 would be sufficient to restore the dystrophin reading frame.

 

The focus at AVI and Prosensa must be on getting their lead compounds though clinical trials; otherwise the companies will go out of business before establishing revenue streams to support further research.  However, academic researchers are targeting other exons and finding good targets for steric-blocking oligos.  I know Steve Wilton of Perth has been screening oligos thoughout the dystrophin transcript.  Once the first exon-skipping oligos are approved, the information generated by the academic sector will combine with the work at the pharma companies to guide development of the next therapeutic exon-skipping molecules; currently the work is divided up.  There has been work in the academic sector on the sort of multi-exon-skipping therapeutic you describe.  If the regulatory process were less onerous perhaps oligos targeting several more exons would be going though trials now, but costs are very high and the companies can only bring one oligo though trials at a time.

Thanks again! Let's see what comes out of the combined efforts of academic researchers and the pharma industry.

Jon Moulton said:

Good day Bernardo,

 

I agree - since your son is already skipping exon 7, oligos targeting exons 6 and 8 would be sufficient to restore the dystrophin reading frame.

 

The focus at AVI and Prosensa must be on getting their lead compounds though clinical trials; otherwise the companies will go out of business before establishing revenue streams to support further research.  However, academic researchers are targeting other exons and finding good targets for steric-blocking oligos.  I know Steve Wilton of Perth has been screening oligos thoughout the dystrophin transcript.  Once the first exon-skipping oligos are approved, the information generated by the academic sector will combine with the work at the pharma companies to guide development of the next therapeutic exon-skipping molecules; currently the work is divided up.  There has been work in the academic sector on the sort of multi-exon-skipping therapeutic you describe.  If the regulatory process were less onerous perhaps oligos targeting several more exons would be going though trials now, but costs are very high and the companies can only bring one oligo though trials at a time.

As I understand it, AON's have been created in the laboratory to skip every skippable exon.  The hurdles are regulatory.  This could be circumvented for rare exon skips with perpetual IND trials.  I don't agree with waiting on the results of this trial.  The results of this trial does not tell us anything about the effectiveness of skipping other exons.  Does a poor result on 51 mean the others will never see a human trial?  It shouldn't.



Jon Moulton said:

Good day Bernardo,

 

I agree - since your son is already skipping exon 7, oligos targeting exons 6 and 8 would be sufficient to restore the dystrophin reading frame.

 

The focus at AVI and Prosensa must be on getting their lead compounds though clinical trials; otherwise the companies will go out of business before establishing revenue streams to support further research.  However, academic researchers are targeting other exons and finding good targets for steric-blocking oligos.  I know Steve Wilton of Perth has been screening oligos thoughout the dystrophin transcript.  Once the first exon-skipping oligos are approved, the information generated by the academic sector will combine with the work at the pharma companies to guide development of the next therapeutic exon-skipping molecules; currently the work is divided up.  There has been work in the academic sector on the sort of multi-exon-skipping therapeutic you describe.  If the regulatory process were less onerous perhaps oligos targeting several more exons would be going though trials now, but costs are very high and the companies can only bring one oligo though trials at a time.

Hi Keith,

 

If someone gets the perpetual IND working, that could provide a method for getting legal exon-skipping oligos prior to completion of traditional clinical trials.  That's a reasonable potential method for speeding up access.  I like your argument: "Does a poor result on 51 mean the others will never see a human trial?  It shouldn't."  I've heard the argument made that successful completion of one clinical trial for an exon-skipping oligo will make the perpetual IND strategy for other exon skippers more palatable to regulators, but you argue well for why we shouldn't wait. The strategy needs to be applied once so others may follow.  This may prove to be a great method, perhaps the only method, for getting treatment for mutations requiring less common skips for which even an expedited preclinical/clinical testing process may be a commercially insurmountable barrier.

I don't know if this was discussed in Baltimore.  At one point there was discussion on this board about exploring what the costs would be to produce AON's and run a perpetual IND.  The viability of the concept hinges on that, since there'd be no insurance coverage.  Does the AON cost $100k a year to produce, or $5k, in a non-profit setting?

Hi,

We found that my soon have stop mutation on exon 18 ( c.2227C>T;Gln743x)

I do not know anything about this mutation and whether the Ataluren could help.
If you have any knowledge about this mutation, or have your boys write.
Thanks

Hi Kieth,

 

The cost will be closer to $100K than $5K.  Making the subunits from RNA nucleosides adds much of the current cost, but that could decreased as subunit production is scaled up.  The first generation of exon-skippers will be expensive.  The larger scale the production, the more the cost could be trimmed, but a synthetic molecule with a molecular mass of 8000+ will always be more expensive than small-molecule drugs -- there are a lot of synthetic steps involved in the manufacturing.

 

Hi Andrea,

Ataluren is designed to help ignore premature stop codons during protein production, so a stop codon in exon 18 would be a reasonable candidate for that treatment (but I'm not a clinician, you should consult your physician). 

In the long run, exon-skipping might be a good treatment for that premature stop codon.  To treat this mutation by exon skipping, one could skip exons 17 and 18, removing the stop codon and keeping downstream mRNA sequence in-frame.  However, there are no trials soon-to-start for those exon-skipping targets, so it will be some years before this option might be developed.

Hello Andrea,

 

Ataluren is designed to overcome any stop codon, regardless of the exon. My son has a stop codon mutation in exon 7, so I've been reading all about PTC124 (Ataluren) since I've heard about it 8 years ago. Unfortunately we are all still waiting for PTC, Genzyme and the FDA to get their act together and have that drug approved at once. It is obvious to everybody that at low doses the drug considerably slows down the progress of the disease, by producing some dystrophin. However, the guys responsible for all this suspended the trials just because the primary end-point had not been met by a margin of ONE PER CENT (1%). Now they restarted the trial for boys already enrolled, and I certainly hope that they will stop playing around soon. Nobody says Ataluren is a magic pill, or that non ambulatory boys (like my son Hernán) will start walking again. Everybody knows that the drug manages to produce some dystrophin, thus alowing the muscles to catch up a little bit with regeneration. That is indeed the most dramatic concrete and proven result so far in the fight against DMD. Good luck!
Andrea Ruzic said:

Hi,

We found that my soon have stop mutation on exon 18 ( c.2227C>T;Gln743x)

I do not know anything about this mutation and whether the Ataluren could help.
If you have any knowledge about this mutation, or have your boys write.
Thanks

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