Fixing a Genetic Flaw

Continued from page 1

Hoffman's team worked with Shin'ichi Takeda at the National Center of Neurology and Psychiatry, in Japan, and gave three beagles with a naturally occurring canine form of DMD weekly or biweekly intravenous injections of a cocktail of three different antisense molecules. After several weeks of treatment, the dogs showed noticeable improvements in muscle function tests and symptoms, and their cells produced dystrophin at an average of 26 percent of normal levels. Hoffman says that these levels are similar to those found in human patients with BMD, and "the clinical improvement was about what you'd expect based on what we know about human patients."

A similar approach was tested in rodents and in four humans in 2007, but only as a local injection into muscle cells. This study used a newer type of antisense molecule called a morpholino that binds to DNA but isn't recognized as foreign DNA and degraded in the body, making it possible to deliver the treatment intravenously. Hoffman says this is the first time that researchers have successfully delivered an antisense therapy systemically to alleviate DMD in a larger animal.

"I'm really encouraged by this," says Richard Moxley, a neurologist at the University of Rochester, adding that the study provides important evidence in favor of the idea of shifting the clinical severity of DMD to mimic a lesser disease. Moxley says that the ability to deliver the treatment in a systemic injection is also important for its practical use. However, he says that several questions remain about how well the treatment will translate into humans. The antisense patches did not always work in the dogs as was predicted by studies in individual cells, suggesting that there are still unknown details about how they interfere with transcription.

In addition, because different Duchenne patients are missing different pieces of the dystrophin gene, many would require a combination of different antisense molecules to see benefits similar to those seen in the dogs. Hoffman says that this complication will pose a regulatory challenge and present a test for developing a personalized approach to medicine. He believes that an initial drug could at least target the most common mutation and help about 15 percent of DMD patients.