Fixing a broken gene to improve blood flow
COLUMBIA, Mo 9/1/14 (Beat Byte) -- As the Muscular Dystrophy Association's (MDA) annual Labor Day telethon celebrates its 48th year this weekend, Mizzou researchers have delivered good news for muscular dystrophy patients and their families. 

A Columbia-based team led by medical research professors Dongsheng Duan, Ph.D., and Yi Lai, Ph.D. patented a therapy in August for two types of the neuromuscular disorder:  Duchenne Muscular Dystrophy (DMD), the most common type; and Becker Muscular Dystrophy (BMD), a milder variant of Duchenne. 

The therapy uses various cell-penetrating "delivery vehicles" to repair a broken gene called dystrophin that plays a critical role in muscular function.   The work dates back to at least 2009, when the Mizzou team discovered that dystrophin anchors an enzyme called neuronal nitric oxide synthase (nNOS) to muscle cells.   nNOS produces nitric oxide, a simple molecule that helps cells signal one another.  

Loss of functional dystrophin leads to loss of nNOS in muscle cells, which in turn leaves them without nitric oxide -- and no way to communicate with nerve cells or other muscle cells.   One major symptom is loss of blood flow to skeletal muscles, which are unable to let muscles surrounding blood vessels know when to dilate and deliver more blood.   

In time, the muscles grow weak, atrophy, and die, the typical symptoms of muscular dystrophy.   Death normally follows after several years, as heart and lung function gradually vanishes. 

The Duan-Lai team earlier discovered a way to repair the broken dystrophin, which loses its ability to anchor -- or "tether" -- nNOS to muscle through an inherited gene mutation.   The researchers replace sections of the dystrophin gene known as R16 and R17, which restores funcationality.    "Dystrophins that contain R16/17 show membrane expression of nNOS, while those without R16/17 do not," the team explains in its original November 2013 patent filing

Converting this process into a therapy requires miniaturizing the dystrophin, which is among the longest human genes.  Earlier therapies used miniaturized dystrophin, but without first repairing it with the missing sections.   Those therapies, Duan found, were never successful.   To discover why not, he went on a historical quest, reading long-forgotten research from the 1970s that found ischemia -- loss of blood flow -- was a potential factor in DMD. 

The connection between ischemia and broken dystrophin, however, was not clear until Duan found research dated twenty years later. 

"When I moved through history into 1995, there were papers showing that one of dystrophin's roles is to recruit neuronal nitric oxide synthase [nNOS] to the muscle-fiber membrane," he told the MDA in a 2011 interview.   Nitric oxide dilates blood vessels, improving blood flow.   It was the first clue that nNOS played an important role in muscular dystrophy.  

Later work revealed that muscles lacking dystrophin showed signs of ischemia, but simply replacing dystrophin with its miniaturized counterpart did not work unless it had sections R16 and R17 that tethered nNOS to muscle cells. 

"If you have genes that restore nNOS and some that don't restore nNOS to the membrane, you want to choose the ones that restore nNOS," Duan told MDA, which has supported his work.    
The new therapy's use in humans will be some years off, as further testing in animals, clinical trials, regulatory approval, and further analysis awaits.   Other Mizzou researchers on the muscular dystrophy therapy patent include Junling Zhao and Yongping Yue.  

[Ed. Note:  Actor and comedian Jerry Lewis founded the MDA telethon -- now known as the Show of Strength -- in 1966, but started his lifelong work supporting research to cure the disease in the 1950s.   The MDA was a great and long time support to my family.   My sister died of muscular dystrophy at age 27, with what her neurologists said was a rare case of Duchenne Muscular Dystrophy affecting a girl.   It almost always affects males, and is always eventually fatal. -- Mike Martin]


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