Conversation with Dr. Kole - Duchenne a stem cell disease?

Dr. Ryszard Kole from AVI Biopharma and PPMD President Pat Furlong further reflect on recent findings that Duchenne is a stem cell disease. Read the discussion below, as well as, Pat’s previous blog.

I read with interest your blog yesterday regarding the Cell paper on Duchenne that came out on Monday. I can very well understand the excitement, as well as some possible confusion, that the paper generated among PPMD members and the Duchenne community in general. I believe that your comments helped put the publication in the right perspective.


To characterize Duchenne as only a stem cell disease is not entirely correct.  Without dystrophin, a very large structural protein, muscle cells struggle and eventually die.   Without dystrophin, there is no shock absorber to protect cell membrane from tearing when muscle does its work.  Without it the muscle membrane is vulnerable and the repeated contraction and relaxation of the muscles results in small tears in the muscle membrane. (That’s why the boys should not lift weights, do steps, etc – eccentric exercise increases injury).  These small tears (think of holes in the roof of your home) cause extracellular calcium to leak into the muscle cell.  The muscle cell is unable to handle the overload and a cascade of biochemical events occurs with the end result, the muscle cell dies.  The body tries very hard to repair the damage, recruiting satellite cells also called stem cells, to replace the damaged muscle cells and help with repair.  Because the satellite cells have no dystrophin, they are unable to repair the damage and are subject to the same series of events. Eventually, they run out and the muscles deteriorate irreversibly.


If we think about treating Duchenne, it is reasonable to imagine that by interfering at any step along the way, it should be possible to slow the degradation process.   It might be worth thinking about it in terms of a base hit in baseball.    If you target one or more pathways – you might have a single, a double, or a triple.  Replacing dystrophin restores stability to the muscle membrane – a home run. When this happens the muscle cell survives longer and stem cells do not need to step in and are used up more slowly. So it’s at least a double.


There is an excellent mouse model of severe Duchenne developed previously by Dr. Kay Davies and her group at Oxford that offers additional color on this issue  (; Goyenvalle A, Babbs A, Powell D, Kole R, Fletcher S, Wilton SD, Davies KE. Prevention of dystrophic pathology in severely affected dystrophin/utrophin-deficient mice by morpholino-oligomer-mediated exon-skipping. Mol Ther. 2010 Jan;18(1):198-205. PubMed PMID:19844193).


In mice, if only the dystrophin gene is defective, the disease is mild, animals move around well, and have close to normal lifespan. In Dr. Davies’ mouse, a gene for utrophin, which can compensate for lack of dystrophin, is also knocked out. These double knockout mice have very severe muscular dystrophy, are barely mobile, and survive for no longer than 20 weeks. Healthy mice live for about two years.


This paper, published a year ago, also shows that the treatment of double knockout mice with an oligomer that causes exon skipping in dystrophin mRNA restores production of dystrophin.  The presence of this protein restored mobility of these severely affected animals to almost normal levels and extended their lifespan. These effects were achieved with exon skipping, a method that does not affect the stem cells. There is also a variety of published and unpublished data showing that restoration of dystrophin by exon skipping promotes muscle regeneration and inhibits degeneration, which in turn should reduce pressure on stem cells and regenerative capacity of affected muscles. On the basis of these findings I agree with you and respectfully differ with Dr. Blau and colleagues. In my opinion, in Duchenne muscular dystrophy, dystrophin restoration is essential to enable muscle function and to protect stem cells from early depletion. Duchenne is ultimately and certainly a dystrophin disease.


With Best Wishes,



Ryszard Kole, Ph.D.

Senior VP, Distinguished Scientist

AVI Biopharma

3450 Monte Villa Parkway

Bothell, WA 98021

Ph. 425-354-5199

Fax. 425-489-5933


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Comment by Lisa Mancin on January 17, 2011 at 3:10pm

Soooo much more I could say, but I won't.

Agree to Disagree!

Good Luck, Cheryl

Comment by cheryl cliff on January 17, 2011 at 11:25am

Well then its good for us to say that we respect each others idea of what a parent should do for their sick child and go different ways.  I don't care if you like or disagree with my perceptions of context, it's really no big deal.     

So in an effort to eliminate your confusion, my rambling about taking Alex to docs that specialize in duchenne was to point out that I don't automatically trust just anyone who happens to have the letters MD after their name.  I dig further to determine if that doc has anything to do with my sons disease, have they always worked with duchenne patients, if there have been any lawsuits or complaints in their history and what they are about if something is found, if they comprehend more than I do about duchenne, do they communicate well in person, can I sense their human compassion, are they practicing at an environment of learning & research. 

I'd be happy to consider other options, "outside the box" as you say, when and if practitioners are able to pass that criteria.  If you dig a little further you might find the doctors currently providing stem cell treatments in third world countries comprehend a lot more about just stem cells, one part of duchenne but certainly not the whole package.  Frankly, I suspect those doctors comprehend how to make a buck off the despiration of others more than even having a solid background in stem cells. 

At least when my child takes medication, even deflazacort, I can research the pros and cons in order to determine what the side effects are and make an informed decision in his behalf.  Can't do that regarding stem cell treatments right now but I look forward to having that option in the future when solid scientific data is available. 

Making informed choices for Alex is the best I can give.  He deserves that.   




Comment by Lisa Mancin on January 17, 2011 at 4:05am
Comment by Lisa Mancin on January 16, 2011 at 11:51pm

I don't really like to have discussions with people who take everything out of context, but I will give it one more shot and then I will be done.

Like I said, I have spent hundreds of hours researching, not only stem cells, but also all of the other things you mentioned.  I am very well aware and familiar with all of them.   I did not say that everyone with an MD can provide benefit to your child and I did not say that duchenne experts are in a box. Thinking out of the box means considering other options, of which there are many, including stem cells.   I also did not say  that they can not help my child.  I actually said they do help to keep my child healthy for the time being.  There is nothing unfortunate about it.


The many comparisons you gave seem ridiculous and unnecessary.  I am not sure what your point was, except to say that stem cell doctors are not MD experts.  I never said they were.  They are stem cell experts who happen to treat MD patients as well as other patients. 


Big pharma may not be the only ones looking for $$$$$, but it IS over a 100 billion dollar industry and they do have alot of control over what the many researchers, scientist, doctors, and regulators focus their efforts on.  And the many drugs they provide do not CURE anything.  In fact, they often cause many serious health problems, which you are concerned that stem cells may do.  .  We don't hesitate to give our sons massive doses of Prednisone KNOWING the serious side effects and consequences.  It may help in the short term, but we know that long term use will destroy the immune system (among other things), leaving them vulnerable to many things, including pneumonia.  That is solid data. You can put your son through that?  But I do understand your position and wish you the very best.






Comment by cheryl cliff on January 16, 2011 at 10:31pm

Very glad to hear you have time to relax.    


So, please understand I do read info regarding DMD every day, twice a day, even on days I'd rather be relaxing.  I haven't put all my eggs in the exon skipping basket although I see it as something on the horizon that has good potential, that is why I mention it as something I'd take my son to the UK for. 


Like I said, I believe stem cell science can and most likely will have a great impact too, we're just not there yet.   I also follow myostatin inhibitors, gene therapy, HGH, Idebenonne, Losartin, Utrophin upregulation- despite the recent setback, STS and others. I get loads of information from clearly reliable sources and have been on this planet long enough to realize not everythig in print provides "knowledge".  Not everyone with an MD after their name can or will provide actual benefit to my child. 

I'm not sure what box you see duchenne experts in and sorry they can't seem to help your child.  It's very unfortunate.  But I've never thought it necessary to seek a dermatologist to work on my child's dental issues, or an ortho to perform surgery on his heart.  I don't even send my dog to anyone who doesn't call themselves a vet, and with valid papers in view.  It would seem to me like hiring a hair dresser to seek legal advice when who knows,  there might be a nice political scientist with a recent book who could change the oil in my car too  :)     

Been on this planet long enough to realize pharma companies, researchers, scientists, doctors, regulators and a host of others will have an impact on my childs life and condition, like it or not.  Just giving more stem cells is a very simplified concept of an extremely difficult, complex disease.   Just giving more stem cells could cause serious health issues we aren't aware of because the science is too early, and I can't put my son through that.  And, just giving more stem cells isn't free.  Pharma's aren't the only ones looking for $$$$$$.

I'll wait for solid data.  It's in my son's best interest.  Your son is most likely undergoing stem cell treatments in a third world country which you are uncomfortable being upfront about.  I can't do that to my son but do understand your position and truely wish you and him the very best.   





Comment by Lisa Mancin on January 16, 2011 at 3:41pm

Hi Cheryl,

It sounds like we both struggle with the same issues of every day life.  I can relate to everything you said, except that I DO  make sure to sit, relax and read...and almost everything I DO read has to do with DMD and treatments. That is what I meant by doing something.  What I don't have time for is many of the things you mentioned.  I have spent hundreds of hours researching and reading about all of the possibilities.  I have looked "outside of the box" many times, as I feel that  all of the wonderful doctors that you have mentioned still can't do anything to REALLY help my son, other than keep him as healthy as possible for the time being. 


I really wasn't trying to give you advice, but just share some information that I found interesting. Knowledge is matter where it comes from... even if you don't agree with it.


I do agree with your "eggs in the basket" theory, but I do not plan to put all of our eggs in the exxon skipping drug basket.  If the exon skipping drug is supposed to preserve the stem cells that are already there, why not just give more stem cells???  They are admitting that stem cells are needed, but they want to make sure that a pharmaceutical drug is involved in the process..$$$$$

So, If you are waiting for some solid data regarding stem cells you could have a long wait.  I am sure that they haven't even obtained the "solid diagnosis" on Ryan (the little personal experiment ??? , which you mentioned)which was the hold up on any further information there.  But, that's okay.  We will all continue doing what we feel is best for our sons, because yes, they all do deserve the very best. 


Comment by cheryl cliff on January 16, 2011 at 10:19am

Hi Lisa,

Thank you for your kind words.  Yes, I live for a few grains of positive data as you mentioned.  Right now that's all I have to go on but with that said I won't allow my emotional desperation to take over my childs life.  Glad to read you are among those of us who are doing something and not just waiting on others to come through for our sons.  My husband and I contribute when ever we can and so far we've spent the last 3 years (since dx) advocating in Washington and locally, learning about duchenne and upcoming stragegies, fundraising, donating (tens of thousands), attending meetings, interacting with other parents, communicating with respected scientists in DMD, acquiring & maintaining durable medical equipment, remoodeling our house, interfacing with schools, dr's appts, camp, PT & OT and the daily rigors of a normal routine.  Then we have the recreational aspects of life with decreasing abilities and trying to maintain constant positivity, extended family life with elderly parents.....I wish I had time to sit, relax and read.  I don't.  But if I did- it probably wouldn't have anything to do with DMD or treatments :) 


I too believe in the science of stem cells and see much hope in that as an upcoming treatment.  Since duchenne isn't a one sided disease, placing hope in just one strategy is like putting all eggs in one basket, which can't go well since dmd distroys many parts of a whole.  Yes, stem cells are a large part of that whole and yes, it would be nice to fly somewhere and obtain treatments.  But my son isn't near death this week, he has problems that are being observed and addressed by excellent medical staff I sincerely trust with his life.  Kevin Flanigan/Nationwide Childrens (recently became a new Wellstone Center, yay) and our cardiologists Dr Allen are among the worlds best and the rest of the staff there is amazing. 


I admire the parents or patients who conduct a little personal experiment by doing what you suggest.  I've met a very nice one (Curtis) and respect his family trememdously and communicated with others.  I understand why they do what they do.  From the sound of it your son must be seeking stem cell treatments with Dr Rader.  If so, how is it going?  How long have you been getting treatments?   What benefits have you been able to see so far?  What are the side effects?  How does your son deal with the treatments?  Where do you have to travel and where do you all stay?    If you choose not to say, I understand.  Not everyone wishes to come into the open. 


I appreciate your advice and thanks for that.  However, when you read my posts stating I am willing to fly somewhere to obtain treatments I am mostly referring to going to the UK for exon skipping currently in clinical trials.  I believe skipping will (and is) progressing there much faster then it will here in the states for a variety of reasons and encourage other parents, who can't wait,  to do the same.  I would fly somewhere for stem cells if and when more information becomes available.  But right now not enough solid data is available for me to jepordize my child's health by seeking treatments from someone who doesn't specialize in DMD. 


My son deserves nothing less than the very best.  But then, don't they all?

Comment by Lisa Mancin on January 15, 2011 at 1:00am

  Cheryl, I can sense and relate to  your feelings of frustration and the need for " a few grains of positive stuff" as you have stated.  Your son is 12 and mine is 13.  We have reached a certain point where our patience is short and a feeling of desperation has taken over.  Since the beginning, I have always felt better when I am the one acitvely DOING something --not just waiting on other people to do something,  It gives me a certain sense of control over the situation--and alot of hope.  Like you have said, it is important to focus on the positive.  Our kids definately deserve a Mom who can breathe deep and not live in negativity 24-7.


As you know, I have been interested in stem cell treatment for a long time.  I am not a Dr. or an expert of any kind, but I personally feel that stem cells are the answer. It gives me alot of hope to believe that there IS an answer--maybe it will for you too. I do not plan to wait years for an exon skipping drug that will also delay deterioration of stem cells.  We don't have years.   I am putting my hopes into the direct administration of stem cells through an i.v. --just like a blood transfusion--based on blood type--no rejection problems--and it reaches all muscles and organs in the body.  There are already people who have gone to other countries and had these treatments--using American M.D.'s.  Since you mentioned that you are open to using other options which are  available NOW.. I thought you  might be interested in the book- Blocked in the U.S.A. The Stem Cell Miracle by William C. Rader, M.D.  There are many Success Stories in the book, including 2 DMD patients.  Maybe it will give you that shred of hope you are looking for. 

Comment by Ofelia Marin on December 22, 2010 at 1:36pm
Cheryl, I understand, as you know there are other potential treatments in the pipeline and some might get here before exon skipping for the less frequent mutations. It is still unclear to me what type of benefit these first chemistry exon skipping drugs will provide and if it will be enough to get them approved, I just did not see much data in DMD boys proving either way at this point. Next year might make things more clear. Of course, I hope they will prove effective and I still believe that there is hope that our sons will have a different future.
Comment by cheryl cliff on December 22, 2010 at 1:31pm
PS, sorry Ofelia if I sounded a little edgy previously.  It's just that lately I've been running out of grains of positive stuff and I read Pat's response to me as a glass half full.  Now after reading your post my nerves are back on edge, not shooting the messinger here,  but damn! 

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