Myotonic Dystrophy Are we too narrow or do we need to expand the focus?

As many of you know there is substantial research now underway for drug therapies for Myotonic Dystrophy. Drug companies are interested as it is the largest population of adult form of muscular dystrophy and it is likely that patients will need to take drugs periodically to insure the condition does not come back.

The most promising of these therapies is Antisense? What is AntiSense you wonder?
Antisense oligonucleotides – short segments of genetic material designed to target specific areas of a gene or chromosome – that activated an enzyme to “chew up” toxic RNA (ribonucleic acid) could point the way to a treatment for a degenerative muscle disease called myotonic dystrophy, said researchers from Baylor College of Medicine and Isis Pharmaceuticals, Inc., in a report in the journal Proceedings of the National Academy of Sciences.

“This is a proof-of-principle therapy that is very effective in cell culture and mice,” said Dr. Thomas A. Cooper, professor of pathology and immunology and molecular and cellular biology at BCM and the report’s corresponding author. “The treatment will have to be refined to deliver systemically in people with myotonic dystrophy.”

One of the foremost researchers in the field Dr. Mahadevan has recently Oct 2012 written an article asking if we are narrowing the focus to early or do we need to continue the basic research to find out more of the small details that will matter with this disease? Following is an abstract of the letter and information he published.

Myotonic dystrophy: is a narrow focus obscuring the rest of the field?

Mahadevan, Mani S.

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Purpose of review: The myotonic dystrophies (DM1 and DM2) are the paradigm for RNA toxicity in disease pathogenesis. The emphasis of this review will be on recent developments and issues in understanding the pathogenesis of DM1 and how this is driving the accelerated pace of translational and therapeutic developments.

Recent findings: RNA toxicity in myotonic dystrophy is now associated with bi-directional antisense transcription, dysregulation of microRNAs and potentially non-ATG-mediated translation of homopolymeric toxic proteins. The role of other RNA-binding proteins beyond MBNL1 and CUGBP1, such as Staufen 1 and DDX5, are being identified and studied with respect to their role in myotonic dystrophy. New functions for MBNL1 in miR-1 biogenesis might have a clinically relevant role in myotonic dystrophy cardiac conduction defects and pathology. Advances are being made in identifying and characterizing small molecules with the potential to disrupt CUG–MBNL1 interactions.

Summary: Mechanisms of RNA toxicity are moving beyond a simplistic ‘foci-centric’ view of DM1 pathogenesis as a spliceopathy due to MBNL1 sequestration. Therapeutic development for myotonic dystrophy is moving rapidly with the development of antisense and small molecule therapies. Clinically, significant emphasis is being placed on biomarker discovery and outcome measures as an essential prelude to clinical trials.

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1 thought on “Myotonic Dystrophy Are we too narrow or do we need to expand the focus?

  1. Antisense makes sense to me but I worry that mice are not men and results in mice are not always equivalent to results in humans. After all both species are separated by millions of years (probably about 100 million give or take) and though hopes are raised and the focus narrowed to MMD1 the likelihood of finding an antisense therapy that will work in humans remains small. Also the loss of muscle strength is not ameliorated using current antisense tools. I hope that I am wrong but years in the pharmaceutical industry make me cautious.

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