Rein in rogue RNA to treat muscular dystrophy

U. ROCHESTER (US)—Researchers have discovered a way to block the genetic flaw at the heart of a common form of muscular dystrophy. The results suggest a new avenue for therapies that may essentially reverse symptoms.

Because scientists believe that potentially all symptoms of myotonic dystrophy—the most common form of muscular dystrophy in adults—flow from this single genetic flaw, neutralizing it could potentially restore muscle function in people with the disease.

The researchers at the University of Rochester Medical Center used a synthetic molecule to break up deposits of toxic genetic material and re-establish the cellular activity the disease disrupts.

“It also demonstrates the potential to reverse established symptoms of the disease after they have developed, as opposed to simply preventing them from getting worse,” says neurologist Charles Thornton, senior author of the study and codirector of the Wellstone Muscular Dystrophy Cooperative Research Center.

Myotonic dystrophy is a degenerative disease characterized by progressive muscle wasting and weakness and prolonged muscle tensing. Currently there is no medication to halt the disease’s progression.

In recent years scientists have discovered that RNA, a versatile molecule that is very similar to DNA, is a central player in myotonic dystrophy. RNA serves a vital function by relaying the genetic information from the nucleus—the protected area of the cell that houses DNA—out to the main body of the cell, where the instructions are used to build proteins. Every gene produces its own RNA, usually in multiple copies, and every RNA is a genetic blueprint of its parent gene.

The surprising aspect of myotonic dystrophy was that the genetic defect leads to production of a toxic RNA—the first example in human genetics in which RNA was cast in the role of molecular perpetrator. The errant RNA has a toxic effect because it grabs onto and holds hostage certain proteins, preventing them from carrying out their normal functions.

“An unexpected byproduct of research on myotonic dystrophy was that we were forced to change our ideas about the role of RNA in genetic disease,” says Thornton. “Once we adjusted to this new concept, we realized that the prospects for developing treatment might be unusually good. No essential component of muscle is missing, but some important proteins are in the wrong place, stuck on the toxic RNA.”

The synthetic molecule the Rochester team used mimics a segment of the genetic code and is designed to bind to the toxic RNA and neutralize its harmful effects by releasing the captured proteins. When injected into the muscle cells of mice with myotonic dystrophy the molecule found its way to the cell nucleus, broke up the deposits of toxic RNA, freed the captive muscleblind proteins, and ultimately improved the function of the muscle cells.

The researchers specifically observed a restoration of proper electrical control in the cells, which is a convenient way to monitor the condition. However, because the hostage proteins play a role in a myriad of other cellular functions, they believe that this treatment will ultimately alleviate other aspects of the disease as well.

“Based on our current understanding we would predict that by releasing the proteins held hostage, many of the symptoms of the disease may potentially be corrected by this approach,” says neurologist and study coauthor Thurman Wheeler.

The authors are quick to point out that major hurdles must be overcome before this compound can be tested in humans. Specifically, a better delivery system must be developed to get this or a similar compound to where it needs to go in the body, and the potential side effects must be carefully analyzed. However, having established a general concept of what a treatment for myotonic dystrophy may look like, researchers believe that the next steps in developing an effective drug should go faster.

The study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute of Neurological Disorders and Stroke, the Muscular Dystrophy Association, and the Run America Foundation. Results were published in the July 17 issue of the journal Science.

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