Another Muscular Dystrophy Mystery Solved; Scientists Inch Closer to a Therapy for Patients

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, a protein essential for muscle cell survival and function. Absence of dystrophin starts a chain reaction that eventually leads to muscle cell degeneration and death. 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 that can keep muscle cells healthy after exercise.

"Dystrophin not only helps build muscle cells, it's also a key factor to attracting nNOS to the muscles cells and helping nNOS bind to the cell and help repair it following activity," said Lai, a research assistant professor in the Department of Molecular Microbiology and Immunology. "Prior to this discovery, we didn't know how dystrophin made nNOS bind to the cells. What we found was that dystrophin has a special 'claw' that is used to grab nNOS and bring it close to the muscle cell. Now that we have that key, we hope to begin the process of developing a therapy for patients."

In their study, Lai and Duan found that two particular sections of the dystrophin gene must be present for nNOS to bind to the muscle cells. The sections of the gene, known as "repeaters 16 & 17," contain a "claw" that can grab nNOS and bring it to the muscle cells so that it will bind and repair any damage from regular use. Without this "claw," nNOS doesn't bind to the cells and the damage is not repaired, leading to further problems associated with muscular dystrophy.

The other key to this puzzle is dystrophin. If the protein is not present in the body, no "claw" exists and nNOS would never make it to the muscle cells. For years, scientists have been attempting to find ways to make the body manufacture more dystrophin, and thus get more nNOS to the muscle cells. Duan and Lai said the answer might lie elsewhere.

"Everybody, including those individuals with muscular dystrophy, has another protein known as 'utrophin,'" said Duan, a professor of molecular microbiology and immunology. "Utrophin is nearly identical to dystrophin except that it is missing repeaters 16 & 17, so it cannot attract nNOS to the muscle cells. In our study, we were able to modify utrophin so that it had the repeaters, and thus, the ability to grab nNOS and bring it to the muscle cells for repair. Our study was completed in mice; if we can do the same thing in larger animals, we could eventually have a significant therapy for humans with this devastating disease."

The early-stage results of this research are promising. If additional studies, including large animal studies, are successful within the next few years, MU officials will request authority from the federal government to begin human drug development (this is commonly referred to as the "investigative new drug" status). After this status has been granted, researchers may conduct human clinical trials with the hope of developing new treatments for the disease.


Views: 1449

Reply to This

Replies to This Discussion

Can any one get the full journal artical ?

Very interesting, lets hope this can be develop faster so can apply to every kind of mutation.
So what bearing does this have on exon-skipping drugs that target mutations including a deletion of exon 45? (Such as Eteplirsen and Drisapirsen - currently targetting deletions 45 - 50 amongst others). Will they produce dystrophin but have little or no clinical benefit due to the absence of nNos??

I think this article shows that we are still too far from understanding this complicated disease because nothing confirmed about the nature of this disease!!! do you think that?

I am too worried that time is running quickly


i think this could lead scientists to produce more effective drugs and also change the currently in progress drugs like smtc1100,eteplirsen and  so on.

we must be hopeful.

The first thing that this would benefit is gene therapy, where a full dystrophin gene cannot fit in the viral vector a mini-dystrophin gene is created for the task, this study tell researchers the most important parts of the gene that need to be included in the mini-gene.

Second for exon-skipping drugs depending on the deletion, there maybe a chose to skip one exon over another, keeping the exon that connects to nNOS. For example for a 45 deletion, exon 44 OR exon 46 can be skipped.

Third, new and improved drugs that activate nNOS by itself or with existing drugs in the pipeline. (viagra and cialis work by turn up nNOS and hopefully will work well with utrophin upregulation and exon-skipping where the nNOS connection is missing)

Does anyone have ideas on natural ways to gain nNOS in cells? With foods, vitamins, or treatments of some sort? In the article it says, “One of these "helper" molecular compounds is nNOS, which produces nitric oxide that can keep muscle cells healthy after exercise.”
I see that they sell ‘nitric oxide’ supplements. Could this be good to use? It says that it helps blood flow.
Some things could be tried and may help a little. Lets do some research and see we can come up with that may be helpful. 

hct-1026 is a good candidate to increase nitric-oxid

please review latest reseraches about:

Cedars-Sinai research: Preclinical muscular dystrophy data shows promise

Mehrzad, thanks for sharing this. I think that there must be also a natural way of increasing nitric oxide in the blood, lets see what can I find and come back eith some news

Bacillus subtilis that the artical talks about is a probiotic that you buy.  This could be tested on DMD right now
mehrzad haidari said:

 (European Journal of Pharmacology, 2013) The Nitric Oxide-donor molsidomine modulates the innate inflammatory response in a mouse model of muscular dystrophy

Paola Zordan, Clara Sciorati, Lara Campana, Lucia Cottone, Emilio Clementi, Patrizia-Rovere Querini, Silvia Brunell

Inflammation plays a crucial role in muscle remodelling and repair after acute and chronic damage, in particular in muscular dystrophies, a heterogeneous group of genetic diseases leading to muscular degeneration. Defect of nitric oxide (NO) generation is a key pathogenic event in muscular dystrophies, thus NO donors have been explored as new therapeutics for this disease. We have investigated the immune-modulating effect of one of such drugs, molsidomine, able to slow the progression of muscular dystrophy in the α-Sarcoglican-null mice a model for the limb girdle muscular dystrophy 2D, sharing several hallmarks of muscle degeneration with other muscular dystrophies. α-Sarcoglican-null mice were treated with molsidomine and drug effects on the inflammatory infiltrates and on muscle repair, were assessed at selected time points. We found that molsidomine treatment modulates effectively the characteristics of the inflammatory infiltrate within dystrophic muscles, enhancing its healing function. Initially molsidomine amplified macrophage recruitment, promoting a more efficient clearance of cell debris and effective tissue regeneration. At a later stage molsidomine decreased significantly the extent of the inflammatory infiltrate, whose persistence exacerbates muscle damage: most the remaining macrophages displayed characteristics of transitional population, associated with reduced fibrosis and increased preservation of the muscle tissue. The dual action of molsidomine, the already known NO donation and the immunomodulatory function we now identified, suggests that it has a unique potential in tissue healing of chronic muscle damage. This, alongside its already approved use in human, make of molsidomine a drug with a significant therapeutic potential in muscular dystrophies.

Reply to Discussion


Need help using this community site? Visit Ning's Help Page.



© 2022   Created by PPMD.   Powered by

Badges  |  Report an Issue  |  Privacy Policy  |  Terms of Service