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 cheryl cliff on December 22, 2010 at 12:06pm

I understand we are talking about possiblilties Ofelia.   I appreciate you putting it in your terminology because you can/do help increase comprehension for Paul and I and most likely others.   

After seeing Alexanders progression of late I thought we might be losing the option for skipping in his case.  But with Dr Flanigan said Alexander would be a good candidate for skipping, and with the addition of exon skipping possibly delaying deterioration of stem cells I feel we can breathe a little deeper.  For me breathing a little deeper isn't the same as singing hallelujah there is a cure!  You see some of us (speaking of myself here) need to focus on the positive, even dig deep to find a drop of it somewhere in the poison. Living the Duchenne life provides enough negativity 24-7 therefore having a shred of hope no matter how small, breathing deeper occasionally, is all we get and so I take it that way.  I deserve it, my sons deserve having a mom who can breathe now and again.  Its our reality and how we manage.      

Yes it will take years for skipping to arrive here but as you already know Paul and I don't have any intention of waiting for meds to reach the USA.  There are other options available for us and others.  Will any of this come in time to save my son's life?...only God knows. 



Comment by Ofelia Marin on December 22, 2010 at 10:31am

Cheryl, I do not think that it’s clear at this point, it depends on so many factors including chemistry used, efficiency obtained etc. In theory, it should benefit.

Keep in mind that the “benefit” obtained using PMOs might/is expected to be lower than with PPMOs on skeletal muscles, diaphragm and heart. Dr Kole’s example using dKO mice and restoring “mobility of these severely affected animals to almost normal levels and extended their lifespan “ used PPMOs. Who knows when/if PPMOs will enter clincal trials and how many years from now they can be approved. Judging by how slow AVI moves the PMO skipping 51 along I do not have high hopes for PPMOs skipping several exons during the next few years.

Comment by cheryl cliff on December 22, 2010 at 10:00am

So, reading that exon skipping should still provide benefit not only for Alexander but others who are considered "older" is wonderful news!!  The best present for which Paul & I are extremely grateful!!!

Merry Christmas Pat,



Comment by Pat Furlong on December 22, 2010 at 8:54am

Hello Everyone,

First, Ophelia you have it right- we won't know until we see what happens in trials  And keep in mind, it is not simple because impact (negative or positive) will also depend on many other factors such as degree of muscle loss, fibrosis, genetic modifiers, etc.   All strategies are aimed at slowing degeneration, extending function.  None of these approaches help the heart and we know increasing /extending function increases burden on the heart.  

Alejandra, Ace-031 inhibits more than myostatin.  It acts on the entire pathway and is suggested to recruit stem cells from the periphery (not just muscle satellite cells), decrease fibrosis and up-regulate utrophin.  I'm not sure how to interpret your statement 'same thing as the aging process between 0-5' unless you are suggesting that Ace-031 is expected slow degeneration based on boys 0-5 (actually 7ish) are considered in the 'golden years' where cell turnover is so rapid that they actually improve in function (and refine muscle function).  During this time, parents are often mislead to imagine that a certain supplement or activity is the reason for improvement and it is actually due to cell turnover and refinement of motor skills.

Cheryl, I think you would find general agreement that stem cell therapies are behind exon skipping technology. for a lot of reasons.   One major reason is that the morpholinos have been in man, so a great deal is known about safety and toxicology.   Stem cells have 3 major issues - delivery to every muscle cell in the body, insuring the type of stem cell delivered actually makes muscle cells (rather than adding fat for instance, increasing damage) and insuring the immune system does not reject the cells.   
There has been discussion around the truncated Dystrophin proteins produced with exon skipping technology and a sense that the boys have revertant fibers, where these 'skipping' mistakes naturally occur, suggesting the immune system will not see the shortened (truncated) Dystrophin protein produced with exon skipping as foreign.  
This year, the scientific track of our annual meeting will focus on two areas:  1) heart and 2) immune response to muscle degeneration, to dystrophin and to vectors (gene therapy)

You are right Cossu is working on a protocol to deliver mesoangioblasts to muscles in the leg.   You are probably aware Jacques Tremblay has been working single muscle delivery for the last 20 +/_ years using myoblasts.    There is a lot of discussion around limb-delivery (UNC has been working on this, Jerry Mendell -Follistatin) and others.   And because of the issue around delivery of cells to every muscle of the body or major muscles of legs/arms/trunk - this will take time.

And I think I have already answered your question Alejandra.  In the first years of life boys' muscles are degenerating.  It just does not look that way because they are turning over muscle rapidly (growing) and because they are also refining their motor function (learning how to use their muscles better).  For the observer, that looks like there is no degeneration and that they are getting stronger.  

I hope this helps.   Please let me know.

Warm regards, Pat

Comment by Alejandra Lagffer on December 21, 2010 at 8:49pm
For what I know ace 31 makes the same thing as the aging process between 0-5 years old is this right?
Comment by Ofelia Marin on December 21, 2010 at 6:54am

Jonathan, with any myostatin inhibitors there is the possibility of stem cell depletion in the long run. I asked Dr. Mendell about it and the answer was not clear enough for me (just like any other question I ask about the new treatments)...we'll only know in time.

Comment by Jonathan on December 21, 2010 at 12:27am

Peter Novak said in another post - ACE 031 is supposed to have big muscle (hypertrophy) not hyperplasia,so the stem cells will not be involved as in the monkey was injected with Follistatin in Jerry Mandell trial

I dont know where he got this info from, so dont know the validity.

Also I thought ACE-031 was more about inhibiting myostatin? The way I understood ACE-031 was that it will make the muscles stronger and larger without actually fixing the problem.

Wouldnt this just mean that boys would be able to be mobile for longer and push the windows out further? In the end the same problem is still occuring and eventually with time they will lose ambulation etc.

Comment by Ofelia Marin on December 20, 2010 at 8:17pm

I would like to know, if anyone can explain, why it is thought/hoped that ACE-031 will not generate stem cell depletion... other than the fact that it will hopefully upreg utrophin in a significant way.

Comment by cheryl cliff on December 20, 2010 at 5:36pm

Thank you Dr Kole for explaining things.  Previously to reading this post, I thought exon skipping might arrive too late to benefit my son, who is now 12.  From this it seems that if exon skipping comes ahead of stem cell death then it we can expect benefit.  Please correct me if this isn't so. 

Comment by Alejandra Lagffer on December 20, 2010 at 5:31pm

and why does the first six years of the boy there muscle are no degenerating? why at six they are not capable to regenerate there muscle cells?

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