A little dystrophin
is better than none

MDA grantee

Dongsheng Duan at the University of Missouri at Columbia, and colleagues, have found that mice with only 5 percent of the normal level of the muscle protein dystrophin were slightly stronger, at least temporarily, than mice without any dystrophin.

The study, published online April 1 in the American Journal of Pathology, may have implications for potential gene-based and other therapies for Duchenne muscular dystrophy (DMD) that only partially restore the needed dystrophin protein to muscles.

Until now, it’s been assumed by most experts that about 20 percent of the normal level of dystrophin would be needed for therapy to be meaningful in boys with DMD, a disease in which dystrophin is missing in muscle cells.

But when Duan’s team bred mice that not only had very low dystrophin levels but made a slightly smaller-than-normal version of the protein, they were surprised to see stronger grip strength and more resistance to contraction-related injury than they did in mice without any dystrophin at all. However, they also noted the muscle protection was limited and wore off when the mice got old.

In humans, the researchers note, 30 percent of a normal dystrophin amount is thought to be sufficient to prevent MD, and 20 percent has been believed to result in mild MD. It now appears that levels perhaps even as low as 5 percent of normal might be beneficial, even if they aren’t curative.

Various compounds to inhibit myostatin have been proposed as possible treatments for muscle degeneration, and one such compound, MYO-029, recently was tested in a clinical trial in adults with various muscular dystrophies. MYO-029 is an immune-system protein (antibody) that blocks, or neutralizes, myostatin. It was found safe in patients. (See Research Updates, May-June 2008).

Xiao and colleagues inserted
the gene for MPRO (myostatin
propeptide), which blocks myo-
statin, into the shells of type 8 adeno-asso-
ciated virus (AAV8). They then injected
the AAV8-MPRO combination into a
vein in mice with Duchenne muscular
dystrophy (DMD).

After only one injection into each mouse, they saw an increase in skeletal muscle bulk and strength, as well as larger and more uniform muscle fibers and less inflammation and scar tissue than in untreated DMD-affected mice.

However, on a treadmill test, the treated mice showed less endurance than their untreated counterparts. The investigators say they have no clear explanation for this, but they note that stronger muscle force doesn’t necessarily mean better endurance and that blood-vessel abnormalities in these mice also might be a contributing factor.

MDA grantee Dongsheng Duan’s study suggests that even a little dystrophin might offer some benefit in DMD.

Xiao, who has received MDA funding for other gene-transfer research, says the long-lasting nature of a gene transfer approach is an advantage over using an antibody or other protein. “Since we used AAV to produce the propeptide in a continuous way in the mice, any newly synthesized myostatin in muscle will be neutralized,” he said.

“When you use a neutralizing [disabling] antibody against myostatin, you have to keep administering it to the patients frequently to keep an effective concentration required to block myostatin activity. When using a gene therapy approach with AAV, the mice — or patients — produce their own propeptide 24 hours a day, seven days a week.”

Xiao Xiao and colleagues found blocking myostatin with myostatin propeptide genes increased strength and bulk but decreased endurance in mice with DMD.

Gene transfer benefits mice
with myotubular myopathy

Anna Buj-Bello at Louis Pasteur University in Illkirch, France, with a team that

 

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Gene transfer may be
a good way to block
myostatin

Transferring the gene for a myostatin-blocking protein into muscles might be a good way to block this muscle-growth-limiting protein, say researchers coordinated by Xiao Xiao at the University of North Carolina at Chapel Hill, in a report published in the March issue of Human Gene Therapy.

Mouse experiments by MDA grantee Alan Beggs and colleagues suggest injecting myotubularin genes could be effective in myotubular myopathy.