I’ve just spent two weeks in a row on the road at different meetings—first the Health Research Alliance (HRA) meeting in New York and then the Muscular Dystrophy Association meeting in Las Vegas.


HRA is an organization made up of most of the major non-profit funders of health research -- the members meetings are designed to keep us up to date on the latest trends in research and funding and to allow us to learn from one another.  I chair the HRA Working Group on “Funders of Drug and Other Therapeutics Development” which met over breakfast in New York.  For this working group meeting we invited three industry guests, including Stu Peltz from PTC Therapeutics, to help us understand what kinds of collaborations are most helpful to industry.  Stu provided the example of PPMD’s “Project Catalyst” collaboration as a good way for nonprofit groups to jump start drug discovery and keep companies focused on the disease areas in which they are most interested.

I also moderated a session on building sustainable patient registries that featured the Director of the NIH Office of Rare Disease Steve Groft and Barry Byrne from the University of Florida as speakers.  I spoke in this session as well and discussed how Duchenne Connect contributes data to the TREAT-NMD global registry, which is in turn used by industry to plan multi-national clinical trials.  There was a lot of interest in this model from the other organizations present.

After HRA in New York, I was home for a few days and then headed to Las Vegas for the first MDA scientific meeting (in the past MDA has had “Clinic Directors’” meetings, which featured a mixture of clinical information and scientific presentations and were typically closed to outside participants).  The meeting was attended by about 300 participants including MDA grantees from all areas of neuromuscular research and outside attendees including representatives from many biotech and pharma companies (AVI, Prothelia, Summit PLC, Phrixus and Pfizer to  name a few).  While I was there I had side meetings with many of these companies.

There were quite a few DMD-specific presentations at the meeting covering the gamut from exon-skipping to gene therapy to stem cell therapy. 

First, Steve Wilton talked about his success in being able to skip exon 17 and 18 with a cocktail of oligos and then he described how he is using the oligos on normal mice to delete certain exons in the dystrophin gene and then see how functional the mouse is—it’s a way to determine if removing specific exons will result in a mild or more severe muscle weakness and may give us some clues about the results of removing those same exons in humans.  For example, deleting exons 68 and 69 should have produced severe symptoms in the mouse but the results were surprisingly mild.  He made the point that exon-skipping will likely have to be treated as personalized medicine and approaches tailored for different mutations, potentially even those that delete the same exons.

Aurelie Goyenville of the University of Oxford reported her results in using an adeno-associated virus to carry the code for oligos that induce skipping rather than injecting the oligos directly.  The advantage is that you theoretically only have to deliver the sequence for the oligos once and then the muscle cells will manufacture the oligos for you.  The downside is that if there are any safety issues you can’t easily stop treatment.   Clinical trials are planned in 2012.  Dr. Goyenville’s group is also working on a multi-exon skipping strategy that would remove exons 45-55 and be applicable to about 63% of boys with deletions.  To skip that many exons she had to generate 11 sets of oligos.  So far she has tested the ability to skip exons 51-55, which proved difficult and the ability to skip exons 45-51, which proved easier.  Next she will combine all of the oligos to skip all the exons between 45 and 55.

Gulio Cossu talked about his plans to conduct a phase I/II clinical study in Italy using stem cells from healthy donors called “mesangioblasts” (which come from the linings of blood vessels), to build new muscle.  Siblings who are complete HLA matches are being used as cell donors and there will only be three participants in the study (45 boys were screened).  Each participant will be used as his own control so the selected boys were monitored for 18 months to get a good baseline on disease progression before starting the protocol.  The study will take place in two phases starting with an infusion of donor mesangioblasts through the femoral artery and then followed by two “multi-district intra-arterial” infusions.  The primary outcome is safety but the investigators will also be looking at efficacy in the form of contractile force.  The first participant in the study was infused a week and a half ago.

John McCall, who is affiliated with the work at Children’s National Medical Center in Washington D.C. talked about the ability of new drugs to target the therapeutic pathways that are activated by steroids without triggering the side effects of steroids.  Eric Hoffman’s company Validus has a molecule that both stabilizes the membrane and inhibits an inflammatory pathway that seems to be important in muscle weakness.  The group is planning clinical studies of this drug in 2012.

Stan Froehner from the University of Washington talked about results on muscle and heart strength using the Sildenafil (Viagra) and tadalafil (Cialis).  Both drugs inhibit enzymes called phospodiesterases and increase the amount of a molecule called cyclic GMP, which can combat some of the symptoms of DMD, but it’s not yet clear which drug might be the best to use.  Tadalafil is a more stable, longer lasting drug than Sildenafil, but in preliminary studies it didn’t perform as well as Sildenafil.  Clinical studies are currently underway to test both drugs in older boys and young men with DMD and BMD.

Jeff Chamberlain talked about results in his lab using adeno-associated virus serotype 6 (AAV6) to deliver a minidystrophin gene throughout the bodies of mice, noting that the results lasted up to two years in the heart but were less impressive in the skeletal muscle.  He speculated that different doses of vector (the modified virus carrying a therapeutic gene) might be required to deliver genes to different types of muscle.  In older mice delivering the minidystrophin gene stops further progression but doesn’t bring back full strength.  Chamberlain discussed plans for a human clinical trial using AAV with immune suppression, starting with an intramuscular injection first to measure safety and persistence of the minidystrophin, and then moving to intravascular delivery of isolated muscles, then limbs and then multiple delivery sites for whole body treatment.  He thinks that people will probably need repeat administration over time.

Zejing Wang from the Fred Hutchinson Cancer Center delivered a m minidystrophin gene via a modified virus to the leg muscles of golden retrievers who lack dystrophin using multiple injection sites and found that the minidystrophin could be seen in muscle cells up to two years after the treatment and the dogs showed some improvement in gait and the angle of the hock (ankle).

Dennis Guttridge of the Ohio State University College of Medicine talked about his work with NfkappaB, another potential therapeutic target for DMD. He has developed an inhibitor of NfkappaB that improves the look and function of diaphragm muscle in mice that lack dystrophin and also improves diaphragm and heart function in more severely affected mice that lack both dystrophin and utrophin.  Preliminary safety results suggest the inhibitor has low toxicity.

Jas Seehra of Acceleron discussed the phase I data that supports the ACE-031 study in DMD (presented previously) and Justin Fallon provided an update on progress in developing biglycan to recruit utrophin to the membrane to compensate for the loss of dystrophin.  Jachinta Rooney of the University of Nevada (works with Dean Burkin) presented evidence that Prothelia’s laminin 111 compound is effective in a mouse model of merosin-deficient congenital muscular dystrophy.

Anyone who has questions about any of these presentations is welcome to contact me directly—if I don’t have the answer I’ll try to find it for you!



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Comment by Sharon Hesterlee on October 14, 2011 at 7:09am

Hi Ambrish:


I believe that Dr. Cossu is probably infusing the cells through the arteries at different points.  I will be at the World Muscle Society meeting this week, but I just checked and I don't see Dr. Cossu listed on the agenda.  I will make some inquiries with his fellow Italian investigators to see if there is any update on the progress on this study.


Also, if your son's deletion can be put back into frame by skipping just one exon (sounds like 55 in your case) then that would be the preferred way to go.  There has been some talk about developing oligos to skip multiple exons, but this would be a strategy for treating more deletions with the same set of oligos and it may be a trade-off. 

I will report back on the World Muscle Society meeting just as I have the meetings covered in the blog post, above.  Check back in about a week and a half for that update!



Comment by Ambrish Kapadia on October 14, 2011 at 12:25am

Hi Sharon


I am Ambrish Kapadia from Mumbai India , My son Khush is 4 yr 5 months old is DMD . We found abt his disease when he was 18 mts old .


We appreciate your hard and devotional work for our community . We just live in hopes that something wil  turn our sons around  .


I was reading yr above post dtd 7th April 2011 . Could u pls elaborate what Dr Cossu means by   “multi-district intra-arterial” infusions .


My son is having exon deletions from 52 to 54 and as per Dr Steve Wilton he is eligible for exon skipping 55


Will any of multi exon skipping approach be applicable to him .Just thought of this when I read "multi-exon skipping strategy that would remove exons 45-55  " in yr above post


Will lookforward to hear from u at earliest


Thanks Ambrish

Comment by Donna Taylor on April 8, 2011 at 10:48am
Thanks so much for the detailed update Sharon.
Comment by amit gupta on April 7, 2011 at 4:58pm

Thanks for the summary Sharon. I found a link to the abstracts for anyone interested -


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