Antisense RNA Relieves Symptoms of Myotonic Dystrophy

The molecular basis for myotonic dystrophy, the most common form of muscular dystrophy in adults, has been traced to the accumulation of a toxic form of RNA that binds to and inhibits essential muscle cell proteins.

Investigators at the University of Rochester Medical Center (NY, USA) worked with a transgenic mouse model to study the interaction between RNA containing multiple CUG (cytosine-uracil-guanine) repeats and the important muscle cell regulator protein muscleblind-like 1 (MBNL1). In myotonic dystrophy, CUG RNA binds MBNL1 and disrupts the muscle's ability to contract and relax.

To study this protein/RNA interaction the investigators created an antisense RNA (the morpholino antisense oligonucleotide, CAG25) that binds to the strands of CUG RNA and prevents them from blocking MBNL1 activity. Results published in the July 17, 2009, issue of the journal Science revealed that injections of CAG25 into the muscles of mice with myotonic dystrophy dissolved deposits of toxic RNA, liberated the bound MBNL1, and ultimately improved the function of the muscle cells.

"An unexpected byproduct of research on myotonic dystrophy was that we were forced to change our ideas about the role of RNA in genetic disease,” said senior author Dr. Charles Thornton, professor of neurology at the University of Rochester. "Once we adjusted to this new concept, we realized that the prospects for developing treatment might be unusually good. No essential component of muscle is missing, but some important proteins are in the wrong place, stuck on the toxic RNA. As compared to conventional drugs that work on proteins, antisense oligonucleotides work on RNA. They have been around for 20 years, but only recently is their full potential being realized. They provide great flexibility and they can be developed rapidly.”

"This study establishes a proof of concept that could be followed to develop a successful treatment for myotonic dystrophy,” said Dr. Thornton. "It also demonstrates the potential to reverse established symptoms of the disease after they have developed, as opposed to simply preventing them from getting worse.”

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University of Rochester Medical Center