How to fight a hydra

Myotonic dystrophy type 1, the most common form of muscular dystrophy, is like a hydra, attacking the body in several ways. That’s why it’s significant news that researchers at Illinois report that they’ve added new capabilities to an experimental drug agent to counter the disease’s pathology in three ways.

“We’ve rationally designed something to target multiple pathways, which is contrary to the traditional thinking in medicinal chemistry, where you have one target, one drug,” said University of Illinois chemistry professor Steven Zimmerman, who led the research with graduate students Lien Nguyen and Long Luu. “People are slowly discovering that drugs that hit multiple targets are actually better.”

Efforts to treat DM1 are in their infancy. The experimental drug agent enhanced by Zimmerman’s team to attack DM1 in three ways team previously defeated only one of DM1’s many modes of action. The team reports its findings in the Journal of the American Chemical Society.

DM1 (but not Duchennes muscular dystrophy) results from a genetic error that causes expansion of a region of a particular gene, called DMPK. Mutant DMPK genes often continue to expand, amplifying the health problems that can result. No drugs are available to treat DM1, which afflicts an estimated one in 8,000 people worldwide.

Scientists are gradually learning how the disease impairs cells. When mutant DMPK is converted into ribonucleic acid (RNA), which plays various roles in protein synthesis, it causes a cascade of problems in protein production, Zimmerman said. Proteins are critical to the function, structure, and regulation of body tissue and organs.

“Dozens of other proteins become dysregulated,” he said. “There’s a chloride channel that causes heart arrhythmias. There’s an insulin receptor that, when it’s dysregulated, gives diabetic symptoms.”

In earlier work, Zimmerman and his colleagues developed a compound that stopped the mutant RNA from binding to the protein MBNL, which regulates RNA processing. But the disease has other means of creating havoc in cells, researchers have since found. For example, the cell translates the mutant RNA into proteins that also turn out to be toxic. And the mutant RNA interferes with the function of other proteins besides MBNL.

“The disease is like a hydra,” Zimmerman said. “You cut off one of its modes of action and we learn about two more that need to be dealt with.”

Nguyen and Luu tackled this problem by modifying earlier work to create multitarget drugs that are small enough to get easily into cells. They found that the new compounds have three modes of action: They stop mutant DNA from converting into RNA, they prevent RNA from attaching to MBNL, and they destroy mutant RNA, a process that is slow but appears to be effective in in vitro experiments.

The most potent compounds the researchers developed reduce levels of the mutant RNA in cells that replicate the pathology of DM1. The new compounds also reversed two symptoms of the disease in a fruit fly model of DM1.

“The new compounds would need to work effectively in mice and pass preclinical benchmarks before they can be tried in humans,” Zimmerman said. “It is encouraging that a different approach using a DNA analog is already in clinical trials in human patients.”

The advantage of the new agents under development in Zimmerman’s lab is their small size, he said.

“Small molecules are much easier to make than larger compounds, they are easier to get into cells and their potential for getting into the brain is higher,” he said.

The research team also included Shaohong Peng and H.Y. Edwin Chan of the Chinese University of Hong Kong and U. of I. graduate student Julio Serrano.The National Institutes of Health and the Muscular Dystrophy Association supported this research.

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