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MD Breakthrough - What to Make of It

Whenever I hear the words "MD Breakthrough', my heart skips a beat. Is it really? Often, it is in reference to a study in the mdx mouse. We can cure mice. But people are not mice... just ask Victor Dubowitz. And when the 'breakthrough' talks about a young man with Duchenne, it feels like we are all standing at Attention!

Over the last couple of days, many of you have seen a news story that recently aired about a young man named Ryan. I wanted to share with you my thoughts about this story. For those of you who have not seen this piece, check out the story by following this link: http://www.kake.com/home/headlines/69538137.html.

I have watched the video of Ryan (by Jemelle Holopirek) several times and admit to some skepticism. To be quite honest, I have a lot of skepticism. My own sons were in the myoblast transfer trials of long ago, receiving some extraordinary number of donor myoblasts in their major muscles. It did not work, not at all. There was a moment when I thought I saw something, when Chris and Patrick did something or said something that seemed to suggest improvement. But there was nothing. And I used the same words "feels better," "seems stronger," etc. All generalities that cannot be measured.

I admit to some bias and for that reason, I wanted to get some answers. I have called the 800 number for Dr. Neil H. Riordan, the specialist featured in the story who is working from Costa Rica, and I am waiting on a return call. The number is answered in the US, and the person answering promised he would relay the message and have them get back to me.

Conceptually, stem cells make sense. The goal would be to deliver sufficient numbers of stem cells, to all of the muscles in the body, or at least the major muscle groups and make sure they integrate with existing muscle cells. The would potentially replace what is lost and if all that works, one might expect, over time, to see improvement.

But - and there is always a "but" - I have any number of questions.

We know this is difficult. Myoblast transfer trials were done in the late 80s and 90s. Jacques Tremblay continues with his myoblast transfer trials in Canda, now moved to limb delivery. Cossu (Italy) is moving toward limb delivery with mesioangioblasts. Gillian Butler Browne is working on stem cells. Lee Sweeney has just requested a small amount of money from us to expand some of his stem cell work (adult-derived stem cells). Barriers to stem cell delivery have been discussed in a variety of forums over the years. For Duchenne, and many other conditions, stem cells are suggested to be the Holy Grail, but it just has not been as easy as hoped for. Some years ago, we sponsored Marie-Therese Little at the Fred Hutchinson Center in Seattle, working on stem cells in the dog model. The barriers included identifying the specific type of stem cell, engineering it to ensure it would make muscle, delivery and rejection. And what does the immune suppression protocol look like? Loads of questions and progress for sure, but not magic.

The video describes three treatments over a year and a half with 46 shots into every major muscle group that resulted in a muscle biopsy with "100% dystrophin levels."

As a community we have to ask the difficult questions. Some of them include:
* What muscle did they biopsy? How was the level assessed?
* What was Ryan's functional ability before the transplant? How has he improved? His wonderful friend Clint (thank heaven for friends like Clint!) described 'neck and trunk stronger' and 'balance better' and 'gained 30 lb.' On the video, Ryan moved only his hands/forearms. And increased weight may not signifiy increased muscle mass and circumference of a specific muscle does not mean increased strength.
* Muscle biopsy - who did the staining? Quantification of dystrophin?
* Transplanted cells - cells from Ryan's sister and donor umbilical cords. What is the immune suppression protocol? Any concerns regarding graft vs host rejection?
* Function: What tests pre- and post- were done to document benefit?

It seems to me Dr. Riordan would do well by convening a meeting with researchers and physicians, including leading experts in the field like Cossu, Gillian Butler-Browne, Terry Partridge, Lee Sweeney, Jerry Mendell, and others. He could then describe his research, procedure(s), data, and outcomes in detail answering a wide range of questions.

I hope I do not sound overly negative. But I have been through this with a wide range of treatments and promises made to our community. And my frustration is not with Dr. Riordan. I hope, just like all of you, that his work is the "breakthrough" this report claims it to be. I just wish the media would understand that words such as "breakthrough" should be used with caution because the reality is often different from the message, and it is their responsibility to ask questions and get substantiated answers before rushing on air.

I will try to contact Dr. Riordan again and look forward to talking to him and getting more answers for all of us. As always, I will share any information I get.

Warm regards,
Pat

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Comment by Govind on January 23, 2012 at 8:54pm: Hi Pat: new to this site...really wonderful with a lot of useful information. What is the latest on stem cell therapy and efforts of folks like Dr. Riordan, Cossu ?
Thanks,
Viny

Staff Comment by Pat Furlong on June 4, 2011 at 10:11am: http://community.parentprojectmd.org/profiles/blogs/duchenneconnect...

Staff Comment by Pat Furlong on June 4, 2011 at 10:09am: Yes, Vanessa Rangel Miller posted the results.

Comment by Benjamin's Dad on June 3, 2011 at 10:57pm: Are there any updates to this story? Were the test results ever posted?

Comment by Lisa Mancin on March 20, 2011 at 7:08pm: Hello Pat,

Thanks so much. I look forward to the information!

Sincerely,

Lisa

Staff Comment by Pat Furlong on March 20, 2011 at 3:34pm: Hello Lisa,

yes we do have the results of his testing. We have written up the information and plan to circulate it through our clinical advisors, Ryan and his family. I am hopeful we will post the information sometime this week.

Sincerely,

Pat

Comment by Lisa Mancin on March 20, 2011 at 3:22am: Hello Pat,

I wondered if you had found any answers to the questions you had mentioned on your February 3rd post, regarding Ryan's test results. I was interested to know if there was any new information from PPMD on the stem cell issue. Thanks so much!!

Comment by amit gupta on February 4, 2011 at 12:36pm: Pat, thanks for your post. You mentioned in your blog above that your sons had myblasts and you did not notice any benefits. Is it your perception that some -ve side effects were noticed as a result of the transfer or just that there were no +ves. Thank you for sharing.

Staff Comment by Pat Furlong on February 3, 2011 at 5:32pm: Amit, there are so many factors to include federal policies on stem cell research, the public's view of stem cell research and its implications, FDA regulations and other factors. Long ago in my career, I was involved part of the transplant team at OSU. We have come so far in whole organ transplant, but we had to learn so much over the last 35+ years and now it is routine... all except for the fact that we do a boatload of studies to determine compatability, use sophisticated immune protocols. The transplant teams are amazing and operate like a well rehearsed orchestra.

For Duchenne, we would need to identify the right type of cell. Cossu uses mesoangioblasts. Tremblay uses myoblasts. So, what is the 'right' cell? How will you deliver it? How will you insure that whatever the number of cells (probably billons) gets into muscle and into every area of the muscle and then every muscle of the body or at least major muscles? And if you are able to deliver to major muscles, what happens to the auxillary muscles. Will they hold up to the burden? How will you make sure that the cell you have delivered understands it is to make muscle rather than (for instance) a fat cell? And how will you prevent the immune system from recognizing that these cells you have delivered are not 'self' and send in specialized cells to get rid of them?
Duchenne is extraordinarily complex and I think we may not yet know some of the questions.

By the end of February we will have Ryan's data. I am hoping this will shed some light on some of these questions or maybe just add to our current list of questions.

Staff Comment by Pat Furlong on February 3, 2011 at 4:55pm: Hi Again,

The tests are done to answer the following questions.

1. What is Ryan's diagnosis

2. Are his sister's stem cells evident in his muscle -i.e we arelooking for donor DNA in Ryan's muscle.

3. Are other members of the family carriers?

How will this data inform PPMD's research invesments in the future? Let's wait for the results and discuss.

And you are right, there is a growing body of research on delivery and immune response, currently the major delivery pathway is bone marrow, blood or nerve - targeted tissues as opposed to, for instance every muscle of the body.. There are immune protocols used in bone marrow transplantation and whole organ transplant are quite useful and serve as a basis for the discussion for work in DMD. The idea here is that whoever does a trial will need to thoughtfully consider an immune protocol and in DMD, this has been considerable discussion as it is anticipated that there will likely be significant variability due to degree of immune response to muscle degeneration and cell death. Keep in mind, the immune response kicks in in varying degrees, at various time points, individual variation (is considered why some do not respond to steroids) and recently Mendell and others suggest some boys may produce an immune response to revertant fibers. It is just not simple and there is a lot we do not know.

. So, the short answer is that the growing body of evidence in stem cell transplantation will enable Cossu and others to build upon the base of knowledge and apply it to Duchenne. But that this approach is still very early days in stem cell transplant for Duchenne. We have not yet delivered stem cells to a single muscle, confirmed that they are in place in sufficient numbers to have an effect, let alone delivery to a limb or the entire body.

It makes perfect sense theoretically, it is just that the devil is in the details.