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Freeing MBNL1 protein
from toxic RNA helped
mice with MMD1-like
disease

Researchers at the University of Rochester (N. Y.) Wellstone Muscular Dystrophy Cooperative Research Center have identified a compound that has the potential to be developed into a treatment for type 1 myotonic dystrophy (MMD1, or DM1).

The compound, dubbed CAG25, is an “antisense oligonucleotide,” a type

of construct that’s used to block RNA, a close chemical relative of DNA.

In the current experiments, the antisense oligonucleotide was given to mice with a disease resembling human MMD1. The researchers wanted to see whether it would counteract any of the effects of MMD1 by sticking to abnormally long RNA and freeing a protein called MBNL1 that would otherwise become trapped in it.

Charles Thornton, who co-directs the MDA clinic at the University of Rochester Medical Center, coordinated the research team, which published its findings July 17, 2009, in the journal Science.

The Wellstone Center at the University of Rochester has had funding from MDA and the National Institutes of Health.

Freeing MBNL1

CAG25

In type 1 MMD, extra-long pieces of RNA form hairpin-like structures, which stick to and trap MBNL1 protein molecules. Thornton and colleagues believe their CAG25 molecule stuck to the abnormal RNA, opening up the “hairpin” and releasing the trapped MBNL1 protein.

The hypothesis Thornton’s research group set out to test was whether releasing protein molecules stuck to long strands of RNA would allow the proteins to resume their normal activities and improve symptoms in mice with an MMD1-like disease.

These mice were given injections of CAG25 into one leg muscle and an inactive substance into the same muscle on the other leg. Researchers interpreting the results didn’t know which legs had received CAG25. The CAG25-treated legs showed improvements in myotonia, the inability to relax muscles, which is a hallmark of myotonic dystrophy.

“What we have now is proof of concept that this general approach for treating myotonic dystrophy is potentially effective,” Thornton said, noting that results of the new study should encourage researchers to improve and refine the strategy.

Masking unwanted instructions coaxed synthesis of needed protein in SMA-affected cells

Scientists at three U.S. institutions have used a very small synthetic molecule to correct the genetic defect in cells taken from a person with spinal muscular atrophy (SMA).

The multicenter research team, which published results in the July-August-September 2009 issue of RNA Biology, was coordinated by MDA grantee Ravindra Singh at Iowa State University in Ames. The team also included MDA-supported Laxman Gangwani at the Medical College of Georgia in Augusta.

The molecule the researchers
developed is called an “antisense oli-