IS this the large animal study that muscle regeneration was waiting for

This paper is taking about long term dystrophin production in dystrophic dogs without immunosupression.


Looks to a very strong case and almost as strong as the exon skipping videos of improvement in dogs. Since its taking about dogs and not mice I am all ears if PPMD experts can comment on this.


I sincerly hope the paper does not have a final conclusion that there is lot more work to do






Long-term Engraftment of Multipotent Mesenchymal Stromal Cells That Differentiate to Form Myogenic Cells in Dogs With Duchenne Muscular Dystrophy

Yuko Nitahara-Kasahara, Hiromi Hayashita-Kinoh, Sachiko Ohshima-Hosoyama, Hironori Okada, Michiko Wada-Maeda, Akinori Nakamura, Takashi Okada and Shin'ichi Takeda

Duchenne muscular dystrophy (DMD) is an incurable genetic disease with early mortality. Multipotent mesenchymal stromal cells (MSCs) are of interest because of their ability to differentiate to form myogenic cells in situ. In the present study, methods were developed to expand cultures of MSCs and to promote the myogenic differentiation of these cells, which were then used in a new approach for the treatment of DMD. MSC cultures enriched in CD271+ cells grew better than CD271-depleted cultures. The transduction of CD271+ MSCs with MyoD caused myogenic differentiation in vitro and the formation of myotubes expressing late myogenic markers. CD271+ MSCs in the myogenic cell lineage transplanted into dog leukocyte antigen (DLA)-identical dogs formed clusters of muscle-like tissue. Intra-arterial injection of the CD271+ MSCs resulted in engraftment at the site of the cardiotoxin (CTX)-injured muscle. Dogs affected by X-linked muscular dystrophy in Japan (CXMDJ) treated with an intramuscular injection of CD271+ MSCs similarly developed muscle-like tissue within 8–12 weeks in the absence of immunosuppression. In the newly formed tissues, developmental myosin heavy chain (dMyHC) and dystrophin were upregulated. These findings demonstrate that a cell transplantation strategy using CD271+ MSCs may offer a promising treatment approach for patients with DMD.

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This one's hard for me to understand.  Can someone put it in simpler terms?

What I get is that


1. Mesenchymal Stem cells (MSCs) were added with CD271+

2. Then these were injected (intramuscular) in DLA matching dogs

3. No Immunosupression was given

4. Within 12 weeks dystrophin was found in newly developed muscle tissue


Where I get lost is why the abstract stops here. For large animal study we can load up with these cells and see if there is functional improvement.



Hi Tulika,

This appears to be simple and straight forward.I hope it works. I am also waiting for other PPMD experts for their feedback.



Hi all - I've sent this discussion to the appropriate PPMD staff member who can provide some commentary. Check back soon!


Sorry for the delay in my response--I was traveling earlier this week and I wanted to make sure I had a chance to read the paper thoroughly before I commented.  So, I do think this is significant in that it's been hard to demonstrate long-term engraftment of transplanted cells in the dog model.  I think the only example other than this paper is Giulio Cossu's work (  I have to tell you that the paper concludes with the standard language "further development of this technique is needed" but we are talking about funding a working group to map out a path to move this kind of project into the clinic as quickly as possible so maybe we can give things a "nudge." (or a kick if needed).


The first thing that certainly needs to be done is for another lab to replicate the results--this may seem like a duplication of effort, but too many times we've seen one lab publish findings that can't be duplicated by any other group.  It's a good safe guard measure before we start injecting things into your boys that could just as easily have harmful effects along with the good.  The investigators also reported that the transplanted cells did make some dystrophin, but not very much and they speculated that it might take up to a year to see the full potential for dystrophin expression based on some preliminary data in the dog model.  But the paper is a potentially a big step forward in solving problem number one:  how to keep the transplanted cells alive and happy and making muscle.


Another big step (which would put the findings more on par with the exon-skipping work in the dog) would be to demonstrate that transplanting the cells actually made the dogs stronger.  This hasn't been done yet.  They just looked for engraftment of cells at this point.




Sharon Hesterlee, Ph.D.

PPMD Sr Director of Research


Thanks Sharon.

I had hoped that this one is not about "further development of this technique is needed". However you rightly point out that now that we have some kind of proof of engraftment in DLA matched dogs we can focus on another lab replicating the findings and also doing a comparison of gains vis a vis exon skipping.

I will dig further in this direction.
Sharon - this isn't systemic, either - is it?  What would a therapy like this look like, if it ever came to be?  Multiple injections into every muscle in the body?

Keith, here's a clip and paste of an abstract that I saw a couple of days before yours.  I'm wondering to what degree successful(?) Systemic Delivery techniques like this can be used in multiple studies.



14 - (The American Journal of Pathology, Available online 13 September 2011) Systemic Delivery of Allogenic Muscle Stem (MuStem) Cells Induces Long-Term Muscle Repair and Clinical Efficacy in Duchenne Muscular Dystrophy Dogs  

Karl Rouger, Thibaut Larcher, Laurence Dubreil, Jack-Yves Deschamps, Caroline Le Guiner, Gregory Jouvion, Bruno Delorme, Blandine Lieubeau, Marine Carlus, Benoît Fornasari, Marine Theret, Priscilla Orlando, Mireille Ledevin, Céline Zuber, Isabelle Leroux, Stéphane Deleau, Lydie Guigand, Isabelle Testault, Elisabeth Le Rumeur, Marc Fiszman, et al.   - France

Here, we characterized canine delayed adherent stem cells and investigated the efficacy of their systemic delivery in the clinically relevant DMD animal model to assess potential therapeutic application in humans. Delayed adherent stem cells, named MuStem cells (muscle stem cells), were isolated from healthy dog muscle using a preplating technique. In vitro, MuStem cells displayed a large expansion capacity, an ability to proliferate in suspension, and a multilineage differentiation potential. Phenotypically, they corresponded to early myogenic progenitors and uncommitted cells. When injected in immunosuppressed dystrophic dogs, they contributed to myofiber regeneration, satellite cell replenishment, and dystrophin expression. Importantly, their systemic delivery resulted  in long-term dystrophin expression, muscle damage course limitation with an increased regeneration activity and an interstitial expansion restriction, and persisting stabilization of the dog’s clinical status. These results demonstrate that MuStem cells provide an attractive therapeutic avenue for DMD patients.

Hi Keith:


The Takeda study basically was systemic delivery--they tried intramuscular injection but also injected cells into the femoral artery.  The found engrafted cells in leg muscles and heart muscle.  I haven't seen the paper Eric posted, above, but will try to get a copy of that one today.  I'm also talking to PPMD investigators about setting up a workshop to lay out exactly what steps we need to do to get to the clinic.



Hi Sharon,

 Just curious if you know about the schedule of the World Muscle society this year. Do we have any presentations on canine improvements via stem cell.


Let us know if you have any new leads in this area.


Hi Tulika:


So, the stem cell workshop that I mentioned in my post above is taking place in June in conjunction with the New Directions in Muscle Biology and Disease meeting in New Orleans (it is funded by PPMD).  if there are new animal data they will likely be presented at this meeting.  I'm sure we will post an update on both the main meeting and the workshop.


As for the World Muscle Society Meeting it's schedueld for October in Perth, Australia.  I'm not planning to attend this year but I think Pat is going.



Human Adipose-Derived Mesenchymal Stromal cells injected systemically into GRMD dogs without immunosuppression are able to reach the host muscle and express human dystrophin.
Vieira NM, Valadares M, Zucconi E, Secco M, Bueno CR, Brandalise V, Assoni A, Gomes J, Landini V, Andrade T, Caetano HV, Vainzof M, Zatz M.

We observed that hASCs injected systemically into the dog cephalic vein are able to reach, engraft, and express human dystrophin in the host GRMD dystrophic muscle up to 6 months after transplantation. Most importantly, we demonstrated that injecting a huge quantity of human mesenchymal cells in a large animal model, without immunosuppression, is a safe procedure, which may have important applications for future therapy in patients with different forms of muscular dystrophies.

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