PPMD has recently posted PDFs from the conference presentations recently in San Diego. Link is at the bottom of this message.

In the exon-skipping presentation, on page 23, there was a statment about the recent AVI trial results that surprised me. The context is some possible reasons why after 6 months of treatment there was little or no clear evidence of clinical benefit.

"Study includes older patients, so it may be harder to get dystrophin expression with less muscle left"

This indicates that exon-skipping may not work for DMD sufferers who have reached a certain level of muscle loss. That's the first time I've heard of such a concern about exon-skipping.

  • Does anybody have any other information that discusses this matter? I do not find anything in mouse or dog studies which suggested the more advanced cases benefitted less.
  • Would this same concern apply to other treatments too, or is this something specific to exon-skipping?

I realize there can be no definitive statements about such efficacy, but it is incredibly important to my family to know if the science for one treatment predicts a drop in efficacy for older patients, while another treatment may not.



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For these reasons and more, I have less hope and optimism for exon skipping.  Given exon skipping is focused to only a few exons/subset of boys, FDA hurdles for each formulation, unknown/limited improvements (transform Duchenne to Beckers), etc., I have started to focus on other treatments, such as utrophin upregulation.

Don't misunderstand - I still hope exon-skipping works for our boys.  It just seems like there is a very long road to success for a limited group.  Unfortunately, my son will need two exons skipped, which is even further away and even more unknown results... :(

We just need to find a way to get these studies to move faster!  :)

The reason that exon skipping isn't as likely to work on older boys is because it can't recreate muscle cells that have already been lost - only help regenerate ones that still exist.


Any therapy that enables the muscles to regenerate more efficiently needs existing muscles to work, if that makes sense.


Stem cell therapy is the only thing I've heard mentioned that might actually be able to replace lost muscle.


That's why it's a race against time for all of our boys, and why this process PPMD is helping to push for expedited approval is so important.

My son too is a long shot for exon-skipping. But, for first time ever, there are at least 8 boys out there with more dystrophin accumulating every day due to AVI'S exon-skipping. It's hard to ignore that.

I guess I'd like to understand the science behind it - what makes exon-skipping sensitive to this factor (if this is even true)? That way I can direct our charitable giving to those treatments that do not suffer the same limitations.


Yes. This was said long time ago when Prosensa fist worked on these drugs. The younger the boys are when starting treatment the higher the chance for benefit. If the boys are close to wheelchair then low chance they can improve in the 6MWT. However, I think that it is not that clear what happens to the upper body. Even if the boys are older and do not improve in the 6MWt, this drug might have benefit on the upper body, but that is more difficult to measure I guess.

Also, I remember pre-clinical research showing that a combination of myostatin inhibitor (so increasing muscle mass) and something like exon skipping or gene thereapy would produce better results than exon skipping alone.


Of course, we have all been waiting for more than a year for news about that ACE-031... These days I am so disgusted by the slow progress that I prefer not to think about it anymore.


I have the same understanding as Mindy...


Fibrotic muscle will not be restored with exon skipping, or utrophin upregulation.  The only potential therapy I've heard that might restore lost muscle is stem cells. 

While older boys may not see improvements when put on exon-skipping treatment, I would think we'd see the rate at which they are losing muscle decline, or even stop.

I should be clear:

  • I have no expectation of ANY treatment restoring my son's ability to walk, exon-skipping or otherwise. He's been in a chair 4 years now and his legs are far too deformed now to even consider it.
  • I hope for, but don't really even expect, a treatment to improve his upper body strength.
  • I just want to stop the decline.

The question then becomes: how much fibrosis is too much for a treament which does not regenerate muscle? I gotta think some scientist somewhere must have asked the question already, right!?




 Just to qualify myself im 33 years old with Duchenne.  There is a study http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.... about dystropin levels.  It found "mice with 3–14% dystrophin outperformed mdx mice in the functional tests. Improved histopathology was observed in mice with 15–29% dystrophin and these levels also resulted in normalized expression of pro-inflammatory biomarker genes, while for other parameters >30% of dystrophin was needed.  So to have any chance at improved muscle strength you need at least %30 plus dystrophin levels.  However,  there is no need to rely solely on exon skipping.  If with for example Utrophin upregulation, exon skipping, and Biglycan were combined there should a compounded effect on the Duchenne pathology. A stabilization could be very significant.   There are other ways to maintain function.  Drugs are not all there is.  There is augmentative robotic assistance.  If you guys are on FaceBook please check out my group Robotic exoskeleton for Duchenne.  I have articles and videos of what is for sale and in development.  They have robot arms and ankles and knees for amputees and i can't see why these devices cant be modified to fit on top of Duchenne patients arms and/or legs.  We all want survival and more.  Myself and your sons want freedom of mobility and independence.  Nothing less is the goal.

I think, Halo is going to address this issue. 

"When boys miss this protein their muscles become much more susceptible to damage,' says Blaustein. Physically, they endure a vicious cycle, with an inflammatory response that damages muscles further as well as a fibrotic effect that disables the regeneration of healthy muscles. "HT-100 tips that balance back," he says, with an anti-inflammatory, anti-fibrosis approach that spurs muscle regeneration.

Fortunately, as we all know they have an aggressive timeline.


I read the study you referenced, let me tell you my interpretation and see if it matches yours:

  • In MDX mice, it takes about 30% of normal dystrophin to show improved strength
  • In exon-skipping, only non-fibrotic tissue will experience any increase in dystrophin
  • Thus, if a person has lost 50% of their muscle to fibrosis, an increase in dystrophin 60% of normal level in the non-fibrotic muscle would be required to achieve improved strength

How close am I?



      Well that above 30% is referring to the studies observation that above 30% the biological markers that are different in MDX mice returned to normal levels.   Those normal levels presumably would allow all the muscle cells that were intact to stay that way.  

        What you have to keep in mind is that there are two cellular cycles going on simultaneously in Duchenne patients muscles.  The deterioration of muscle sells creates scar tissue(fibrosis)  which triggers muscle stem cells to repair damaged cells and replace dead cells.  In Duchenne the deterioration rate is so much faster than the regeneration rate.  The stem cells are fighting a losing battle.

        The more dystrophin reintroduced into the muscles the slower the degradation rate becomes.  What has to happen is to increase dystrophin to level where the regeneration rate catches up.  At this level and above the existing cells dont die, the fibrosis starts to be cleared up and the stem cells that come in become stable muscle cells.  Its a cumulative process over time.  Everyone's body knows where muscle mass needs to be and tries to keep you there.  So fibrosis does not mean permanent muscle mass loss.  The studies on all the Duchenne treatments in mice and dogs show that the fibrosis does decrease. 

           I dont think you would have to elevate the dystrophin level to equal or above the percentage loss of muscle mass.  As long as the regeneration rate of new muscle cells is high enough above the degradation rate over time the muscles should repair.    To me 30% and above is needed to stop the decline.  I want to be confident the stem cells arent behind in their work.  

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