A gene therapy shortcut can improve muscle function in mice with a muscular dystrophy-like disease, scientists have found. The trick is injecting an RNA molecule that can help remove the genetic mutation in muscle cells. This allows the gene to be translated into a reasonably functional protein.
Muscular dystrophy, a disease caused by a genetic mutation on the X chromosome, primarily affects boys and comes in several varieties. Sufferers of Duchenne muscular dystrophy--one of the most severe types--can't produce dystrophin, a muscle protein; most die of heart failure or other problems in their early 20s. Introducing the normal dystrophin gene into muscles could, in theory, induce cells to produce dystrophin. But that's difficult because the dystrophin gene is enormous and unwieldy.
In the last few years, several teams have begun testing an alternate approach. Like most genes, the RNA for the dystrophin protein undergoes a process called splicing, in which stretches of so-called “junk” are clipped out. Researchers exploit this step by introducing a short stretch of RNA that is the genetic mirror image of the Duchenne mutation. This "antisense" RNA binds to RNA molecules from the faulty region; as a result, the splicers interpret the mutation as junk and eliminate it. The result is an almost normal RNA. But although the method had garnered good results in petri dishes, the approach hadn't worked as well in animals.
Muscle biologists Qi Long Lu and Terence Partridge at the Medical Research Council Clinical Sciences Centre in London, U.K., and their colleagues decided to combined the antisense strategy with a chemical often used in gene therapy because it is known to improve delivery of DNA into cells. The group reasoned it might do the same for RNA. When the combination was injected into a large muscle in sick mice, it resulted in dystrophin levels that were 20% of normal, compared to none in controls. That was enough for the muscle to carry some weight, and one injection produced dystrophin for 3 months, the group reports in the 6 July online Nature Medicine.
"It's highly encouraging," says neuroscientist Thomas Rando of Stanford University in California. The challenge now, he believes, is to deliver the antisense RNA through the blood, so it becomes integrated into many muscles at once, and modify it to last longer.