Dec. 15, 2008

Revving Up Utrophin Helps DMD Mice

MDA-supported researchers at the Montreal Neurological Institute of McGill University substantially improved muscle health and resistance to mechanical stress in mice with a disease resembling human Duchenne muscular dystrophy (DMD) by increasing production and distribution of the protein utrophin.

The investigators, including MDA grantees George Karpati and Josephine Nalbantoglu, published their findings online Oct. 21 in the Journal of Biological Chemistry.

In their report, they describe how they designed a chemical switch they dubbed zinc-finger protein 51 (ZFP51) that activated utrophin genes, thereby causing muscle fibers to make more utrophin protein and expanding utrophin's location from one small area to the whole fiber.

Utrophin is a protein similar in structure to dystrophin, the protein missing in boys with DMD and in DMD mice. Unlike dystrophin, however, the utrophin gene remains intact in DMD patients and dystrophin-deficient mice, and its protein product has a small protective effect when dystrophin is absent.

However, utrophin is unable to effectively offset the absence of dystrophin, in part because its structure is slightly different, but mostly because there isn't enough of it and it's concentrated in only one place, at the junction of nerve and muscle fibers. In contrast, dystrophin is normally found bordering the entire muscle fiber, and it plays a role in stabilizing the fiber membrane.

When dystrophin-deficient mice were given an injection of ZFP51 genes into one leg muscle and an injection without the ZFP51 gene into the corresponding muscle in the opposite leg, only the legs that received the ZFP51 genes showed benefit. The ZFP51-injected muscles functioned better and had less muscle-fiber destruction. They also showed restoration of a normal cluster of proteins at the muscle-fiber membrane and improved resistance to injury from muscle contractions.

The mice showed no obvious toxic effects from the treatment, although the researchers acknowledge that compounds like ZFP51 would have to undergo extensive testing to ensure they didn't activate genes other than those targeted.

They would also have to ensure that the ZFP genes and the transporters used to deliver them to muscle would not elicit an unwanted immune response from recipients.

"The ZFP is a small protein, and it will probably not be an immune problem," Karpati said. He noted that an improved ZFP gene delivery vehicle (vector) planned for future experiments "would make the immunogenicity (ability to cause an immune response) of the vector negligible."

Nalbantoglu, who coordinated the project, says the studies "highlight the considerable therapeutic potential of artificial ZFPs for treating DMD."