Turning Off Toxic RNA Reverses MMD in Mice

A group of researchers led by Mani Mahadevan, an MDA grantee and associate professor of pathology at the University of Virginia in Charlottesville, has announced that virtually all the effects of type 1 myotonic muscular dystrophy (MMD), at least in mice, can be reversed solely by targeting the toxic RNA associated with this disease. Mahadevan and colleagues published their findings online July 30 in Nature Genetics.

“Fundamentally,” Mahadevan said, “it seems to me, if you have a poison, such as the toxic RNA seen in MMD patients, causing various defects, it’s much simpler in principle to get rid of the poison than to tackle its various effects individually. In the end, you have to tackle the underlying problem.”

To see if this was possible, Mahadevan and colleagues created a new type of MMD mouse model, with extra copies of so-called DNA CTG repeats.

They also integrated an “on switch” into the DNA, which they could activate by giving the mice doxycycline, an antibiotic, in their drinking water.

When the activation switch was turned on, cells in the mice began the normal process of transcribing the DNA CTG repeats into similar RNA repeats but, because of the extra copies, they made about 10 to 15 times the normal amount of RNA.

Within a few weeks, the mice developed all the hallmarks of type 1 MMD: myotonia, an inability to relax muscles; a heart rhythm abnormality known as a conduction block; and fetal, rather than adult, forms of several proteins.

When the doxycycline was stopped, the DNA was inactivated, and the mice stopped transcribing it into RNA. The mice, surprising the investigators, returned to normal in all respects, except in cases where the heart was very severely affected.

“Tissues that you think are irreversibly damaged, like skeletal muscle or heart, we could actually fix,” Mahadevan said. “I was especially surprised that the heart could repair itself, as I had never seen that before.”

Unlike other mouse models of MMD, and unlike humans with MMD, these mice didn’t have clumps of extra RNA and proteins in their cell nuclei, a phenomenon that many investigators see as a key cause of disease manifestations. Nevertheless, they developed an MMD-like condition.

Mahadevan says his mice had RNA pieces that were both necessary and sufficient to cause MMD -- presumably just because there were more of them than normal -- even though they didn’t form clumps.

“If you take away the poisonous RNA the way we do it, by shutting off the gene, no RNA gets made anymore, the muscles get better, and the heart gets better,” Mahadevan said.

On July 24, a group including MDA grantee Maurice Swanson at the University of Florida published different findings about type 1 MMD online in the Proceedings of the National Academy of Sciences.

The Florida group showed that adding genes for a protein known as MBNL1, which is bound up with toxic RNA in clumps in a different MMD mouse model and in humans with the disease, reversed myotonia and restored four muscle proteins to normal.

Mahadevan said that, although this approach might be more feasible for now, it’s correcting only some of the problems caused by the toxic RNA, rather than getting at the root cause of MMD, the RNA itself.

As for how toxic RNA can be targeted in patients, who can’t be engineered with DNA on-off switches, he said, “You might be surprised at how fast targeting the RNA will progress.”