Muscular dystrophy mystery solved; scientists move closer to MD solution

Muscular dystrophy mystery solved; scientists move closer to MD solution
February 26th, 2009 in Medicine & Health / Diseases

Muscular dystrophy, which affects approximately 250,000 people in the United States, occurs when damaged muscle tissue is replaced with fibrous, bony or fatty tissue and loses function. While scientists have identified one protein, dystrophin, as an important piece to curing the disease, another part of the mystery has eluded scientists for the past 14 years. Now, one University of Missouri scientist and his team have identified the location of the genetic material responsible for a molecular compound that is vital to curing the disease.

Duchenne muscular dystrophy (DMD), predominantly affecting males, is the most common type of muscular dystrophy. Patients with Duchenne muscular dystrophy have a gene mutation that disrupts the production of dystrophin. Absence of dystrophin starts a chain reaction that eventually leads to muscle cell degeneration and death. A previous study by Dongsheng Duan, associate professor of molecular microbiology and immunology, discovered a potential delivery method to replace the mutated genes with healthy genes. Following the replacement of these genes, Duan observed that dystrophin production was restarted in animals with muscular dystrophy.

However, while dystrophin is vital for muscle development, the protein also needs several "helpers" to maintain the muscle tissue. One of these "helper" molecular compounds is nNOS, which produces nitric oxide. This is important for muscles that are in use during high intensity movements, such as exercise.

"When you exercise, not only does the muscle contract, but the blood vessels are constricted," Duan said. "nNOS is important because it produces nitric oxide that relaxes the blood vessels, helping to maintain the muscle with a healthy blood supply. If no blood reaches the muscle cells, they will eventually die. In DMD patients, this means the disease will progress as the muscle cells are replaced by the fibrous, bony or fatty tissue."

Since 1994, researchers have known about the importance of nNOS, but have not been able to determine how to produce nNOS in a dystrophic muscle, or a muscle lacking dystrophin. Many scientists have tried to solve this mystery without success. In his most recent study, published Monday in The Journal of Clinical Investigation, Duan and his team identified the location of genetic material responsible for the production of nNOS.

Following the identification of the genetic material, Duan and his team created a series of new dystrophin genes. In their study, they used dystrophic mice to test the efficacy of these new genes. After genetically correcting the mice with the new dystrophin gene, Duan's team discovered that the missing nNOS was now restored in the dystrophic muscle. The mice that received the new gene did not experience muscle damage or fatigue following exercise.

"With this new discovery, we've solved a longstanding mystery of Duchenne Muscular Dystrophy," Duan said. "This will change the way we approach gene therapy for DMD patients in the future. With this study, we have finally found the genetic material that can fully restore all the functions required for correcting a dystrophic muscle and turning it into a normal muscle."

Source: University of Missouri-Columbia

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WOW!!! nNOS is produced in the body by L-arginine. "Nitric Oxide Synthase (NOS) catalyses the formation of nitric oxide (NO) and citruline from L-arginine, oxygen and cofactors" This is great news!

Naomi
This is exciting news and brings the CURE so much closer to becoming a miracle someday!
its wonderful news; lets hope it does'nt take too long for trials to start
What exactly does this mean? I was under the impression that restoring dystrophin production would restore production of nNOS... Does this say that only using that specific mini-dystrophin gene was able to restore nNOS? So, exon skipping for example, will not have the same effect?

This group is not very closed to clinical trials. As a next step, they plan to test their mini-dystrophin in dogs (if I remember correctly).
thats bad news- maybe another 5-10 years
I got it. The paper can be found here:

Dystrophins carrying spectrin-like repeats 16 and 17 anchor nNOS to the sarcolemma and enhance exercise performance in a mouse model of muscular dystrophy
J. Clin. Invest. doi:10.1172/JCI36612

You can access it free of charge.

http://www.jci.org/articles/view/36612/pdf


Looks like R16/R17 (http://www.dmd.nl/DMD_home.html) are needed. They modified their mini-gene to contain those exons.

Ofelia Marin said:
What exactly does this mean? I was under the impression that restoring dystrophin production would restore production of nNOS... Does this say that only using that specific mini-dystrophin gene was able to restore nNOS? So, exon skipping for example, will not have the same effect?

This group is not very closed to clinical trials. As a next step, they plan to test their mini-dystrophin in dogs (if I remember correctly).
when you go into this link is reads
(last modified February 01, 2004) -is that correct?
The link was posted only to be able to see the dystrophin gene repeats at the bottom of the page. It contains description of dystrophin.

Domain sub domain amino acids exons
...
repeat 16 1992-2101 42-43
repeat 17 2102-2208 44-45
repeat 18 2209-2318 46-48
repeat 19 2319-2423 48-50
hinge 3 2424-2470 50-51
...


R Patel said:
when you go into this link is reads
(last modified February 01, 2004) -is that correct?
Ofelia:

What does it mean for Jacob, if anything, who has deletions of exons 42 and 43?

Ofelia Marin said:
The link was posted only to be able to see the dystrophin gene repeats at the bottom of the page. It contains description of dystrophin.

Domain sub domain amino acids exons
...
repeat 16 1992-2101 42-43
repeat 17 2102-2208 44-45
repeat 18 2209-2318 46-48
repeat 19 2319-2423 48-50
hinge 3 2424-2470 50-51
...


R Patel said:
when you go into this link is reads
(last modified February 01, 2004) -is that correct?
Donna,

It doesn't mean anything at this point. This is the key thing from the paper:

In summary, we have identified the dystrophin spectrin-like repeats 16 and 17 as a novel scaffold for nNOS sarcolemmal targeting.
These data suggest that muscular dystrophy gene therapies based on R16/17-containing dystrophins may yield
better clinical outcomes than the current therapies.


Jacobs Mommom said:
Ofelia:

What does it mean for Jacob, if anything, who has deletions of exons 42 and 43?

Ofelia Marin said:
The link was posted only to be able to see the dystrophin gene repeats at the bottom of the page. It contains description of dystrophin.

Domain sub domain amino acids exons
...
repeat 16 1992-2101 42-43
repeat 17 2102-2208 44-45
repeat 18 2209-2318 46-48
repeat 19 2319-2423 48-50
hinge 3 2424-2470 50-51
...


R Patel said:
when you go into this link is reads
(last modified February 01, 2004) -is that correct?
Dr Duan's study is quite elegant. It does two things. First it demonstrates the clear importance of Nitric Oxide as a vasodilator produced by nNOS where and when it is needed due to the localization and signaling afforded by the rod spectrin-like repeat segment. It reinforces work by Drs Thomas and Victor in Dallas (who have been investigating blood flow derangement in DMD/BMD for more than a decade). Also, it shows that a minigene ( one that contains all four critical elements of the dystrophin protein- in contrast to microgenes that are missing COOH elements) can be made with only the 16, 17 spectrin-like segments in the rod portion and still replace the nNOS localizing function. If this works (as always a big IF) an individual patient's genetic defect would be irrelevant because this replacement therapy would help all DMD/BMD patients. The trick now is to test this in large animals and, as with any gene replacement therapy, demonstrate efficient transfection and protein expression as well as safety.
This may take a while.

Another consideration is pharmacologic replacement of NO as a means to blunt the adrenergic vasoconstriction that takes place with muscle use and hopefully spare the muscles from so much hypoxic/ischemic damage. There are drugs and supplements available and in development to help with this and that need to be considered for large animal and human trials. I think that this process will also require addition combinational therapy to help ameliorate the downstream effects from the decreased, but likely persistent, muscle cell injury; since just increased NO alone may not provide complete protection. In other words, hopefully drug combinations which target the upstream effects of nNOS and membrane integrity ( biglycan, integrin e.g.) and the downstream effects of Ca+ overload (debio-025), inflammation, proteolysis, fibrosis, satellite cell exhaustion etc can be rapidly developed while the kinks in the more definitive gene replacement therapies are worked out,
If the minigene therapy proves safe and effective it would obviate the need for the AON therapies which at there heart really only result in BMD, though this mdx study does show that AON therapies that allow for 16-17 segment expression may be the more effective. I hope this makes a little bit of sense for you and helps answer your question.

Jacobs Mommom said:
Ofelia:

What does it mean for Jacob, if anything, who has deletions of exons 42 and 43?

Ofelia Marin said:
The link was posted only to be able to see the dystrophin gene repeats at the bottom of the page. It contains description of dystrophin.

Domain sub domain amino acids exons
...
repeat 16 1992-2101 42-43
repeat 17 2102-2208 44-45
repeat 18 2209-2318 46-48
repeat 19 2319-2423 48-50
hinge 3 2424-2470 50-51
...


R Patel said:
when you go into this link is reads
(last modified February 01, 2004) -is that correct?
I haven't read through all the posts. but I only have this to say from just reading the titile..

Please just hurry up!

Now, I know everything is in the works, studies are being done, and YES I know it takes time...I just every once in awhile want to say..

PLEASE JUST HURRY UP AND GET IT RIGHT!

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