prevalence of each genetic mutation
There is such exciting news lately about the gains made in treatments for DMD. I attended the conference hosted by Action Duchenne in London a few weeks ago and heard representatives speak from AVI, Biomarin and Prosenza. What I find a little puzzling is why two trials are both testing deletion of exon 51. Is that deletion the most prevanlent form of mutation causing DMD? It seems they are going on next to a trial to treat patients with a deletion of exon 50. How do they make these decisions on which exon deletion to test next? Does anyone have any idea?
Replies to This Discussion
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Permalink Reply by Ofelia Marin on
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Skipping 51 would help the highest number of patients ~13%. Preclinical work for skipping 50 was paid by Charley's Fund $5 MM (Charley needs 50 skipped): http://www.avibio.com/news_detail.php?newsId=0038
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Permalink Reply by Jennifer Shumsky on
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I believe that skipping 51 can also work for a group with deletion of 52 (not all of the 52 group, but some of them)
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Skipping 51 restores the reading frame for a deletion of 52.
http://www.avibio.com/duchenne_muscular_dystrophy.php
Jennifer Shumsky said:I believe that skipping 51 can also work for a group with deletion of 52 (not all of the 52 group, but some of them)
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Permalink Reply by MicahsDaddy on
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they are going in the order of the highest population number. the initial test by both prosensa and avi are to make sure that, basically, both technologies work.
after that, the next highest popluated #'s are gonna be covered...which looks to be 50 and 44.
the exons being worked on first are 44 thru 51. my belief is that once the first few are tested and proven affective, the others will move much faster.
i did not read any of the links mentioned above, so if i am am incorrect with my thoughts or if i reiterated anything, plz accept my apologies.
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Permalink Reply by lisa burke on
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It might be worth noting that, in cases of Becker, mutations involving exon 51 are often noted to be 'particularly mild'. This is also why patch 51 was chosen first. Biggest clinical difference/benefit for the first = more leverage to push for/fund the others.
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Permalink Reply by Tina on
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So, here is my dumb question. Why would AVI agree to a skipping trial involving 50 when there is such a small population of these kids. Is this ethical? Don't get me wrong, i'm all about saving a Duchenne kid but it doesn't seem logical to me. How are they going to find enough kids for this trial? WHy not go for a bigger population of kids as in 51. Doesn't the FDA want to see a good number of kids used in the clinical trials and won't they be measuring the outcome of this trial (i.e., strength testing, ambulation, etc.) as a way of knowing if this drug works? Wouldn't skipping another deletion (i.e., 44 or 45) have a better outcome than skipping 50? So, will the FDA be taking in account the outcome of this trial? I guess what I am saying is, should we be looking at the 'bigger bang for our buck' during these first trials and hope the great outcome from all of this will open the flood gates for all of the other "hot spot' deletion areas and the other remaining exons? Please correct me if I am wrong. I would think we would have to put our first 2 good skips first, that's all.
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you're correct, tina. 50 seems to be an exception to the "more bang for the buck" rule of thumb.
i doubt you need an answer to your question for exon 50 though.
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Permalink Reply by Archana on
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This was a pretty shocking information,I guess not every parent may be capable of financing the pharmaceutical industries.I always thought that the Exon skipping should be purely done on the basis of predominant cases.It is unethical if the basic rules is not practiced in finding a cure.Basically if I am wealthy I can let things happen for my son ,if not I can sit behind and just wait for the luck or fate to play a role.Whenever i made donation I never asked which kids will it benefit because I always thought every kids deserves a better life and a cure regardless.I am sorry but I need to vent .
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Permalink Reply by Bains on
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The way this is going, for kids like my son who needs exon 11 skipping, this technology may not even apply. I mean any strategy you take, either you have millions to contribute or you happened to be part of most common mutation, it is in my view unfair to limit the most promising technology to only one or 2 forms of mutations. Every kids deserves a chance at this promise and I think the recent data is showing enough proof of concept that it is time to consider allowing any possible skippable mutations.
Would it not make a better case to FDA if they conduct clinical trials enrolling any skippable patient and providing the proof of benefits?
We certainly donate funds hoping that they(charitable organizations) invest the money fairly and with no bias. Looks like it is time to review whats really going and be smart about our contributions.
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In fairness to Charley's fund, they do invest in other potential treatments for Duchenne kids.
My concern is that I would imagine the FDA would want to see the best outcome from this drug after the first trial here in the states. So, you would want to put your best first one and/or first 2 foward. Dr. Ed Connor at CNMC has this exon skipping theory, "leave no Duchenne kid behind." Meaning, we have got to get this right the first time so hopefully the rest will come later at a quicker pace and perhaps even altogether so parents don't have to worry over if they are carrying the 'Golden Willie Wonka' exon skipping ticket or not.
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Tina,
I do not think they know exactly what mutations will produce the "best" outcome at this point. Looking at existing BMD cases does not provide an accurate answer in my opinion because:
1. Some BMD patients might not be diagnosed due to very mild symptoms
2. Some BMD cases progressing like DMD might have other mutations in the gene (Steve Wilton has a number of examples of in-frame mutations at DNA level progressing like DMD, proven later to actually be out-of-frame at mRNA level)
I do, however, find concerning the fact that AVI wants to test a NEW (supposedly BETTER) chemistry PPMO using an exon where only a very, very low number of patients are candidates for the trial. That might result in enrollment delays and possibly not having a high enough number for Phase III (as requested by FDA). If that happens, extremely important time is lost for ALL boys waiting in line for the next exons.
I just hope that AVI sized the population and has a good plan in place.
Tina said:In fairness to Charley's fund, they do invest in other potential treatments for Duchenne kids.
My concern is that I would imagine the FDA would want to see the best outcome from this drug after the first trial here in the states. So, you would want to put your best first one and/or first 2 foward. Dr. Ed Connor at CNMC has this exon skipping theory, "leave no Duchenne kid behind." Meaning, we have got to get this right the first time so hopefully the rest will come later at a quicker pace and perhaps even altogether so parents don't have to worry over if they are carrying the 'Golden Willie Wonka' exon skipping ticket or not.
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Permalink Reply by Cori on
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I am going to switch the topic a bit for a moment if anyone wants to participate...how many of your sons would become inframe by skipping exon 51? And how many of your boys would become inframe by skipping of exon 50?
Trey has a single point deletion of 52, therefore would become inframe by exon 51 skipping...I guess you could say we are one of the lucky ones if there is such a thing with this diagnosis.
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