http://www.biosciencetechnology.com/News/Feeds/2010/12/products-che...

Any comments on this? Not sure whether to laugh or cry. Would appreciate any insights. Does this mean there's no therapy if our boys are over 3 years old?

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Yes - I read this today too.  Seems like many of the current approaches - ACE 031, exon skipping - etc. don't take this approach.  But, I have seen some DMD boys that have gone to Central America to get stem cell transplants.  We can thank our ex President Bush for slowing down our research on stem cells.  But, I know our current President has lifted some of the obstacles on this.  I don't know enough about how long it would take to get this up and running.  We'd need Pat or others with scientific knowledge to weigh in on this....In some respects - it's gotta be good b/c at least the issue has been identified.  Will it be in time is another issue.....

Char Burke

Arghhh I have written and deleted stuff now for an hour trying to explain my thoughts!

Its like they are playing statistics. they have only shown what they need to for their own argument.

In the end they say its like the body uses up the ability to reproduce muscle cells like a car running out of gas, yet that would mean that all the muscle cells would die off at once and be replaced by connective tissue at roughly the same time.

I think its more a supply and demand issue.  Eventually over time they might run out but I think when a cure is found it wont exacerbate the problem at all as there would still be some ability to replace and repair damaged muscles. Even at an age of 10 there is still muscle function, and a cure would look to preserve that.

Also I think the comparison between mice telomeres and human telomers wasnt really accurate. Although mice telomeres are 3x longer than human telomers, the mice cells dont live 3x longer than human cells.  

Any treatment in DMD will work better on younger kids, less muscle has been lost. That's not much of a relief, I know -  I have 12yr old. But that is not a reason to believe such treatments won't also help older boys too albeit probably less efficiently.

 

This statement at the end of the article seems wholly unsubstantiated by the content: "Treatments intended to restore muscle will likely work only temporarily or not at all. In fact, they are likely to exacerbate the problem by exhausting muscle stem cells more rapidly."


Seems like a big leap from published results. Did I miss something? Neither article explains why a non-stem cell treatment would "exhaust" muscle stem cells.

 

The source of this seems to be from Stanford:

http://med.stanford.edu/ism/2010/december/duchenne.html

 

I'd really like to hear someone with more medical knowledge than me chime in here.  Coming from Stanford University, I'm leaning toward believing that the findings are legitimate.

The second story gives more details, but it is the same thing. Scientists for years (10+) have been trying to find ways to activate telomerase and inhibit it,  as it has concepts in curing cancer and leukemia as a high percentage of cancers have active telmorase. This is why cancer can be fast growing and doesnt die off. It also has been thought about to make cells immortal.

The comment at the end though is very misleading  - "Finding out that this is a stem cell defect is really exciting,"

There isnt a stem cell defect at all. The process is working as it should. The stem cells divide and their telomeres are shortened.

The only thing Im not sure about is whether or not there is some active telomerase somewhere in the mix. I know embryonic cells and germ cells have active telomerase which is why they can divide repeatedly without shortening their life span.
In the end it is plausable what they are talking about however there are a number of other factors which also affect the bodies ability to not be able to keep up with the building and repairing cycle, such as oxidative stress. I think there needs to be a lot more done in this area.
Keith Van Houten said:

I think the most important think is having a "New more accurate mouse model" than the MDX mouse model. This could bring more effective drugs and even speed up drugs to market.  

 

ACE 031 or any drug that increases muscle mass, would draw on the bodies existing muscle stem cell populations. However, using stem cell treatments with ACE 031 may avoid the problem stated in articles(over stated I hope) .

 

Exon skipping, utrophin, stem cell treatments and drugs that slow muscle damage will still work.

 

As for Telomerase, it may be possible activate telomerase making stem cells act young again:

http://www.nature.com/news/2010/101128/full/news.2010.635.html

Lee Sweeney commented on this article over on the main PPMD site:

 

http://www.parentprojectmd.org/site/PageServer?pagename=advancing_r...

 

Mouse model of muscular dystrophy points finger at stem cells

PPMD's Scientific Director, H. Lee Sweeney, Ph.D., reponds to a recent article in Cell.

It has long been appreciated that since the satellite cells of the mdx mouse cannot be exhausted (because of maintained telomerase activity), the mouse has limitations as a model of human Duchenne muscular dystrophy. These limitations result in the mouse receiving more benefit from some therapeutic strategies, such as myostatin inhibition, where the muscles can more successfully regenerate and are stronger, than is likely to be seen in a human. This is not to say that Duchenne patients would not receive benefit from a drug like the Acceleron decoy activin IIb receptor. Likely the drug will promote better muscle regeneration and stronger muscles. However, unlike the mdx mouse, Duchenne patients will eventually run out of satellite cells and then the benefits will be lost. No one knows how long this will take, and patients will likely have better muscle function for a longer period of time than they would if they had no treatment. 

However, it is important to realize that Duchenne is not a stem cell disease and so stem cell therapies do not offer the only possible means of halting the disease. Duchenne is a disease of accelerated damage to muscle that causes the muscle stem cells (satellite cells) to eventually be used up. Only treatments that stabilize the muscle by putting back dystrophin or possibly utrophin so that continuous satellite cell repair is not needed will prevent exhaustion of satellite cells. That is why there is so much work being done to find ways to slow the damage in Duchenne muscle is important, since it will spare satellite cells. Much of the damage comes from inflammatory response and from the development of fibrosis, which is why they are targets for therapeutic development. Indeed, in the face of continuous inflammation and fibrosis, the satellite cells cannot properly repair the muscle and may even contribute to worsening of the disease. Ultimately it will likely take a combination of therapeutic approaches to both improve muscle function and to decrease the muscle damage, inflammation, and fibrosis. Only by addressing all facets of the disease can we slow the rate of using satellite cells and ensure that the satellite cells, or other stem cells, can successfully repair the muscle.

H. Lee Sweeney, Ph.D.
Scientific Director, PPMD

 

Sooooo.... who is right? Stanford declares "it's a stem cell disease" while Mr. Sweeney claims it is not. Is the medical community this far apart on the very basics? They can't both be correct, can they?

 

This is important to me. I have certainly seen differences in opinions on treatment. But I *thought* there was a consensus on the nature of the disease itself. Does this indicate otherwise?

In a way I think they are both right.  If you look at DMD in terms of progression.
 
In younger patients, if you prevent muscle damage or correct the gene, the stem cell population would remain higher or normal. (Mr. Sweeney  position)   
 
In older patients, the stem cell population gets lower and lower till depletion, treatment would be preventing muscle damage or correct the gene and have to include stem cell if you wanted to increase muscle mass.
 
This does not change consensus on the nature of the disease,  lack of dystrophin is the cause.
 
Increasing the length telomeres could be a new drug target for DMD

I would say that Stanford has either been misquoted or it has been taken out of context as this is so far from being correct it isnt funny. Stanford have a point in their discussion about there "may" be an underlying issue for DMD in that there might be a lack of satelite cells once there has been a fix to stop the muscle breakdown process. BUT the comment about it being a stem cell disease isnt correct.

DMD is about missing a protein and the ongoing processes. Stem cells have nothing to do with that missing protein.


David said:

Sooooo.... who is right? Stanford declares "it's a stem cell disease" while Mr. Sweeney claims it is not. Is the medical community this far apart on the very basics? They can't both be correct, can they?

 

This is important to me. I have certainly seen differences in opinions on treatment. But I *thought* there was a consensus on the nature of the disease itself. Does this indicate otherwise?

Hi,

1.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

2.if we find a way to stop fibrosis then no need for stem cells,so they will not be used up

3.ACE 031 is better to combine with approaches that stabilize Cell membrane.

4.The study was published will not necessarily be correct

Keith Van Houten said:

Lee Sweeney commented on this article over on the main PPMD site:

 

http://www.parentprojectmd.org/site/PageServer?pagename=advancing_r...

 

Mouse model of muscular dystrophy points finger at stem cells

PPMD's Scientific Director, H. Lee Sweeney, Ph.D., reponds to a recent article in Cell.

It has long been appreciated that since the satellite cells of the mdx mouse cannot be exhausted (because of maintained telomerase activity), the mouse has limitations as a model of human Duchenne muscular dystrophy. These limitations result in the mouse receiving more benefit from some therapeutic strategies, such as myostatin inhibition, where the muscles can more successfully regenerate and are stronger, than is likely to be seen in a human. This is not to say that Duchenne patients would not receive benefit from a drug like the Acceleron decoy activin IIb receptor. Likely the drug will promote better muscle regeneration and stronger muscles. However, unlike the mdx mouse, Duchenne patients will eventually run out of satellite cells and then the benefits will be lost. No one knows how long this will take, and patients will likely have better muscle function for a longer period of time than they would if they had no treatment. 

However, it is important to realize that Duchenne is not a stem cell disease and so stem cell therapies do not offer the only possible means of halting the disease. Duchenne is a disease of accelerated damage to muscle that causes the muscle stem cells (satellite cells) to eventually be used up. Only treatments that stabilize the muscle by putting back dystrophin or possibly utrophin so that continuous satellite cell repair is not needed will prevent exhaustion of satellite cells. That is why there is so much work being done to find ways to slow the damage in Duchenne muscle is important, since it will spare satellite cells. Much of the damage comes from inflammatory response and from the development of fibrosis, which is why they are targets for therapeutic development. Indeed, in the face of continuous inflammation and fibrosis, the satellite cells cannot properly repair the muscle and may even contribute to worsening of the disease. Ultimately it will likely take a combination of therapeutic approaches to both improve muscle function and to decrease the muscle damage, inflammation, and fibrosis. Only by addressing all facets of the disease can we slow the rate of using satellite cells and ensure that the satellite cells, or other stem cells, can successfully repair the muscle.

H. Lee Sweeney, Ph.D.
Scientific Director, PPMD

 

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