Gene Transfer Corrects Defects In Mouse Model of MMD

MDA research grantee Maurice Swanson at the University of Florida in Gainesville and MDA clinic co-director Charles Thornton at the University of Rochester (N.Y.) Medical Center recently used gene transfer in mice carrying the genetic flaw underlying type 1 myotonic muscular dystrophy (MMD) to restore several aspects of molecular and whole-muscle function.

“Our hope is that this therapeutic strategy will also be efficacious in humans and be an effective treatment for problems associated with myotonic dystrophy,” said Swanson, a molecular genetics and microbiology professor.

Rahul Kanadia at the University of Florida and colleagues who will publish their results online this month in the Proceedings of the National Academy of Sciences, injected genes for the protein muscleblind-like 1 (MBNL1) into leg muscles in the affected mice and found that their myotonia -- inability to relax muscles -- was corrected.

At the same time, the processing of genetic information for four muscle proteins, all of which are known to be abnormal in type 1 MMD, was also restored to normal.

The work is the result of previous studies by these investigators and others showing that MBNL1 is mislocated in MMD-affected cells and therefore kept from doing its normal job. That job, they have also recently discovered, involves throwing a set of developmental switches that allows muscle fibers to change from fetal to adult forms early in development.

In both type 1 (arising from extra DNA on chromosome 19) and type 2 (from extra DNA on chromosome 3) MMD, the MBNL1 protein is kept from its normal function of helping fibers mature because it’s bound up in clumps of extra genetic material and other compounds.

“We corrected some of these problems by flooding a leg muscle with extra copies of the muscleblind protein gene,” Swanson said. “We were able to correct the myotonia and restore production of adult, rather than fetal, forms of four muscle proteins.”

Some structural abnormalities in the muscle fibers persisted, a problem he speculates could be overcome by boosting MBNL1 levels even higher.

In the next phase of the research, the scientists plan to inject MBNL1 genes directly into the bloodstreams of the mice, he said.

“Myotonic dystrophy patients want all their muscles corrected, not just one. One way to get around this problem is to try systemic injections.”

Systemic injections, he said, might correct even the heart problems associated with MMD, which are a major cause of death in this disease, but the strategy will have to pass Food and Drug Administration tests of safety and effectiveness first.

“Basically,” Swanson said, “we have to make sure everything works correctly in mice before we can proceed to human trials. If everything goes well, that will be within a few years.”