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Antisense Approach Kills Toxic Myotonic Dystrophy Transcripts

By Anette Breindl
Science Editor

Myotonic dystrophy leads to muscle weakness – but also to cardiac arrhythmias, diabetes and cognitive disorders. In fact, Charles Thornton told BioWorld Today, "dystrophy is a bit of misnomer" for the disorder, which he considers closest to a neurodegenerative disease.

The disease exists in several different forms, ranging from mild to severe. Currently, it is possible to treat the symptoms and manage the complications of myotonic dystrophy, but there is no cure; no treatment addresses the root cause of the disorder.

But Thornton, who is a neurologist at the University of Rochester Medical Center, and colleagues from Genzyme Corp. and Isis Pharmaceuticals Inc. have managed to beat back the symptoms of myotonic dystrophy for up to a year through relatively short-term treatment with an antisense oligonucleotide.

They reported their findings in the Aug. 2, 2012, issue of Nature.

The paper, Thornton said, is "one in a series of recent important publications suggesting that antisense may finally be coming into its own for neurodegenerative disorders."

So far, he added, all that progress has come at the preclinical level. But in addition to myotonic dystrophy, antisense oligonucleotides have recently shown promise in Huntington's disease and amyotrophic lateral sclerosis, as well as spinal muscular atrophy. (See BioWorld Today, March 14, 2011.)

Myotonic dystrophy is caused by a mutation in the dystrophica myotonica-protein kinase or DMPK gene. The problem, however, is not with the protein kinase itself. In fact, the mutation, which consists of an expanded repeating triplet, is in an intron, so the protein is normal.

DMPK "is produced at lower levels" in individuals with myotonic dystrophy, Thornton said. "But it's not clear that that has any effect, and it's certainly not the predominant effect."

Instead, the dominant effect is that RNA produced from the mutated DNA cannot be normally processed. Instead, it forms aggregates that affect RNA splicing – the cutting and joining of the protein-coding sequence from raw transcribed messenger RNA. Ultimately, changed levels in two splicing proteins, Muscleblind and CELF1, leads to widespread changes in transcription that are toxic to the cell.

Because myotonic dystrophy is a dominant gain-of-function mutation, it is well suited to targeting via antisense knockdown. Silencing the problem copy of DMPK via targeting of the expansion would leave one DMPK copy to produce protein. In many, if not most instances, half the normal amount of a protein is sufficient to keep things humming, or at least limping along, in the affected cell.

Previous attempts at actually making a dent in myotonic dystrophy with an antisense approach, however, had produced underwhelming results. One problem with antisense is that it has been hard to achieve concentrations of the drugs that are high enough for robust therapeutic effects. But Thornton said that his team's paper, along with other recent publications, showed that "by selecting targets with high sensitivity, it may be possible to get therapeutic effects even with the chemistries that are currently available."

In the studies now reported in Nature, that sensitivity was due to the way the antisense they used operated. A so-called gapmer, the drug used by Thornton and his colleagues, induces RNA degradation by the enzyme RNAse H. RNAse H is much more active in the cell nucleus than the cytoplasm – and one consequence of DMPK's mutation is that the RNA tend to stay in the nucleus rather than being exported to the cytoplasm.

Essentially, co-author Frank Bennett, of Isis Pharmaceuticals, told BioWorld Today that extended stay in the nucleus gives RNAse H more time to get at the toxic transcripts. "The longer the transcripts reside in the nucleus, the more sensitive they will be."

Bennett said the team is currently "looking for a drug to take into clinical trials," and hopes to be in the clinic within about a year. He noted that Biogen Idec Inc. has taken an option for a collaboration on discovering and developing such drugs.

In the meantime, Thornton said, his lab's collaboration with Isis and Genzyme has been "extremely productive," and that part of his lab's current work consists of "trying to anticipate" the tools, clinical endpoints and biomarkers that will be most useful in clinical trials "when we get there."