This summer, two MDA-supported research groups published findings that suggest possible approaches for treatment of type 1 myotonic dystrophy (MMD1), a disease in which extra DNA on chromosome 19, when converted by a normal process into RNA, leads to a cellular traffic jam with wide-ranging effects on muscles and other organs. (A similar process happens in type 2 myotonic dystrophy, except that the problem is on chromosome 3 and the gene is called ZNF9.)
Weakness and myotonia (inability to relax muscles), gastrointestinal distress, cardiac problems, cataracts, sleepiness and sometimes cognitive difficulties all appear to stem from the extra RNA in MMD-affected cells.
First, on July 24, a group that included MDA grantee Maurice Swanson at the University of Florida-Gainesville announced online in the Proceedings of the National Academy of Sciences that it had overcome at least some of the effects of MMD1 in mice by injecting genes into a leg muscle.
The genes carry instructions for the protein MBNL1, which is apparently trapped in the nucleus of MMD-affected cells by extra-long strands of RNA and prevented from carrying out its normal functions.
The treated leg muscles recovered from their myotonia, and, at the same time, the processing of genetic information for four muscle proteins, all of which are known to be abnormal in MMD1, was restored to normal.
Some structural abnormalities in the muscle fibers persisted, a problem Swanson speculates might be overcome by boosting MBNL1 levels even higher.
In the next phase of the research, he says, the scientists plan to inject MBNL1 genes into the bloodstreams of mice. “Myotonic dystrophy patients want all their muscles corrected, not just one,” Swanson says. “One way to get around this problem is to try systemic injections.”
Then, on July 30, a group including MDA grantee Mani Mahadevan at the University of Virginia in Charlottesville announced its findings online in Nature Genetics.
Mahadevan and colleagues developed a new mouse model of type 1 MMD, one with many extra copies of the part of the DNA that’s abnormally expanded in this disease. Instead of one long piece of DNA, though, they bred the mice to carry several shorter pieces.
They also integrated a “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 into RNA, 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 MMD1: myotonia; 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 in which the heart was very severely affected.
Mahadevan says the extra RNA pieces in these mice were both necessary and sufficient to produce MMD symptoms, even though they didn’t form the clumps of RNA and protein seen in the human form of the disease and considered by many to be a major cause of these symptoms.
Getting rid of the extra RNA was enough to virtually cure the disease. “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 says. Shutting off the gene may not be possible in people, he notes, but the group has other strategies in mind for targeting the toxic RNA.