Promising step forward toward muscular dystrophy treatment: Symptoms reversed in mice

ScienceDaily (Aug. 1, 2012) Scientists have reversed symptoms of myotonic muscular dystrophy in mice by eliminating a buildup of toxic RNA in muscle cells. The work, carried out by scientists at the University of Rochester Medical Center, Isis Pharmaceuticals Inc. and Genzyme, is published in the August 2 issue of Nature.

After experimental antisense compounds were administered to mice twice a week for four weeks, symptoms of the disease were reduced for up to one year -- a significant portion of a mouse's lifespan.

The investigators say that while the work is an encouraging step forward against myotonic dystrophy, one of the most common forms of muscular dystrophy, it's too soon to know whether the approach will work in patients. But they are cautiously optimistic, noting that the compound is extremely effective at reversing the disease -- whose genetic underpinnings make it particularly vulnerable to an antisense approach -- in a mouse model.

"These results give us strong encouragement about the possibility of developing a treatment that could fundamentally alter the disease. It's an important step on a long path," said senior author Charles Thornton, M.D., a neurologist at the University of Rochester Medical Center who has been pursuing new treatments for the disease for more than two decades.

"But, it's too early to know if this treatment will work as well in people as it did in the laboratory. Unfortunately, in biomedical research there are previous examples of compounds that worked in mice but not in people," added Thornton, the Saunders Family Distinguished Professor in Neuromuscular Research.

About 35,000 Americans have myotonic dystrophy, an inherited disorder that is marked by progressive muscle weakness and stiffness; eventually many patients have difficulty walking, swallowing, and breathing. The disease can also affect the eyes, the heart, and the brain. While there are medications to treat some of the disease symptoms, there is no drug to stop its progression.

The recent progress comes about a decade after several scientists, including Thornton, discovered that the genetic defect that causes the disease works quite differently than most other inherited diseases. In many diseases, a genetic flaw means that an important protein is not made correctly, or not made at all.

But in myotonic dystrophy, the defect results in the creation of an abnormal messenger RNA, which accumulates in the nucleus, getting in the way and stopping other proteins from doing their jobs. One of those proteins is MBNL1, which helps create chloride channels that are important for electrical control of muscles. When that process is thwarted, muscles send errant electrical signals, causing symptoms.

The approach outlined in the Nature paper exploits the roots of the defect, harnessing an enzyme whose usual job is to cut RNA into pieces. Working closely with the Rochester and Genzyme teams, scientists at Isis created synthetic compounds -- short snippets of chemically modified DNA -- that bind to the toxic RNA, modifying it in such a way that it was targeted for destruction by one of the body's own enzymes, RNase H.

With the team's most effective compounds, symptoms in the mice were reversed. The level of toxic RNA was reduced by more than 80 percent; stiffness in muscles eased dramatically; the microscopic structure of muscle was improved; and electrical signaling in muscles returned to normal.

Originally posted here:
Promising step forward toward muscular dystrophy treatment: Symptoms reversed in mice