The Google Alerts were flying last week with Helen Blau’s recent paper about the new mouse model for Duchenne muscular dystrophy that implicates stem cells. The Facebook messages suggested this was something new, some new news. Actually, this is not new. The only thing new is this new mouse model.

The loss of satellite cells in Duchenne is well documented. In early discussions about targeting the myostatin pathway, discussions often referred to the ‘crash and burn’ theory, suggesting that targeting the myostatin pathway would potentially improve strength and extend function, but that it would also increase the ‘drain’ on the satellite cells. What Dr. Blau’s group has done is provided a new mouse model.

If you think about it, the mdx model is the best case scenario for Duchenne and this new model, the worst case scenario. Testing strategies in both models should increase our understanding. In point of fact, many papers suggest that stem cells remain after function is lost – the loss of function related to the amount of fibrosis within the muscle.

The truth of the matter is that Duchenne is not a ‘stem cell’ disease. It is, rather, just one part of the story.

It is often difficult to cut through the lingo to understand what words are used for press releases and what is actual fact. Duchenne is not a stem cell disease, this is an inaccurate picture of what is happening and you only have to look at the boys, at the clinical variability to understand that there is a great deal more going on.

Dystrophin is absent. We are all more than aware of the fact that muscle cells cannot survive without dystrophin. Dystrophin acts as a shock absorber, a connector/communicator (with other proteins), and to some degree, a traffic cop. Without this shock absorber, the muscle membrane becomes fragile, developing small rips, like tiny paper cuts across the cell membrane, causing a cascade of events to include too much calcium overload, decreased nNos (nitric oxide synthase) which in turn makes the capillaries around the muscle constrict, which means less blood supply and less oxygen. And the muscle cell dies.

If that isn’t enough, the immune system, trying to be helpful, comes in to sweep up the mess and because it is so efficient, often does a better job than necessary. Then, in that space, fibrosis replaces what was once muscle.

It is simply inaccurate to say Duchenne is a stem cell disease. It isn’t. Satellite cells are one piece of the puzzle and it is true, they wear out over time. Unlike the mdx mouse with an infinite ability to repair and the Blau mice with no ability to repair – our sons are somewhere in the middle.

Steroids help and while we do not fully understand what they do, we know that they limit the immune response. But then again, our immune responses are variable. Some of us are resistant to bug bite, cough, cold, flu. Others, with a simple bug bite, will get swollen arms and fever. In Duchenne, steroids help most, but not all. It all depends.

In the MRI muscle study in Florida, boys of the same age have varying degrees of fat and fiber. We are not sure why. It all depends.

Craig McDonald is gathering natural history data. He will tell you that steroids and improvements in care (respiratory/cardiac) have changed the natural history, have stretched out the timelines with still significant variability: some boys walking into their late teens, others off their feet at ten.

The reason for clinical variability is not simple – it all depends on the immune response, the fibrosis, the satellite cells – as the loss of dystrophin is the culprit for the diagnosis, but all of the genetic modifiers, the ‘backseat drivers’, are influencing the journey.

The reason to try multiple different strategies, including:

  • Limiting the immune reponse
  • Increasing nNos
  • Decreasing Fibrosis
  • Increasing muscle mass (affecting negative and positive regulators of muscle)

Is because we all agree, to End Duchenne, to stop progression in every individual, at whatever point he (and some she) is in the progression, combined therapies are essential.

Clearly therapies to replace dystrophin or produce a shortened version are ideal and expected to help across these pathways, and for some, these approaches may be nothing short of a miracle (depends on age of intervention, state of disease process, quality of the protein) and for others, less. It all depends.

Today, on we have 50 studies listed. Ten years ago, we had three. It is not enough and never fast enough, but with each paper, each study, we learn, we grow, and we make progress.

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Comment by Deb Robins on December 18, 2010 at 2:54am

It is also inaccurate to imply that the milder symptoms in mice are a new discovery isn't it?  We've been led up the garden path so many times by good results in mice.   Do you think  she means that the ultimate 'miracle' cure will one day come from evolving stem cell research, which is something many scientists mention from time to time? I wonder how well  they know the lay of the land to discount the importance of e.g.  strengthening drug treatments. You should collaborate on a response paper Pat!

Comment by Paul Cliff on December 16, 2010 at 8:52am

How did they find the mouse and dog models?  Is anybody scouring all the monkeys in research labs to find floppy baby monkeys?  Maybe there's some cheaper and easier to keep animal whose muscles work more similarly to those of humans than dogs and mice.  Won't make a difference for a 12 year old like Alex whose going to live or die with what's in the human trials pipeline now, but maybe a better animal model could avoid blind alleys and save some time for the little guys.

Comment by David on December 16, 2010 at 1:26am

Thank you for a concise and direct post! This is the time of year my family donates to advocacy organizations and you've reminded me why PPMD is at the top of that list. You've put at least one parent at ease (relatively speaking of course) tonight. Thanks for that.

Comment by Pat Furlong on December 15, 2010 at 1:45pm

Jason, the blog is not meant to be frightening.  Ace-031 data looks very good. I think the issue is to be mindful of the 'drain' on the satellite cells and the Acceleron/Shire folks are very aware of this.  The good news about ACE-031 is that the effect is dose dependent and, as in all of medicine, finding the right balance to improve outcomes.


Comment by Jason G on December 15, 2010 at 12:52pm

The remarks about some therapies such as ACE31 potentially accelerating muscle wasting are scary .....especially since  my son is in the ACE31 trial.

Comment by Ofelia Marin on December 15, 2010 at 10:49am

My thoughts exactly. I was wondering what's new in that paper except the new mouse model. If you remember they've also used another mouse model to test some of the exon skipping work, dKO mice (utrophin/dystrophin double knockout).

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