MMD Research: Disrupted Disease Process

A small-molecule compound counteracts some of the effects of abnormal genetic instructions in MMD1

by Quest Staff on November 3, 2009 - 10:00pm


A compound that has the potential to be refined and modified into a treatment for type 1 myotonic dystrophy (MMD1, or DM1) has been identified by researchers at the University of Oregon in Eugene, and the University of Rochester (N.Y.) School of Medicine and Dentistry.

Cell Nucleus
In type 1 myotonic muscular dystrophy, extra-long strands of genetic material called RNA trap a protein called MBNL1. Scientists say a compound called pentamidine has shown potential to block some of the effects of the flawed RNA.


The compound, a small molecule called pentamidine, already is approved by the U.S. Food and Drug Administration (FDA) for treatment of a severe type of pneumonia that’s common in people with weakened immune systems, the parasitic diseases leishmaniasis and sleeping sickness, and some yeast infections.

In experiments in mice with a disease resembling MMD1, pentamidine counteracted some of the effects of the abnormal genetic instructions that lead to this disease. However, it did not lead to reversal of myotonia (the inability to relax muscle after use) in the mice.

MDA provided support to Andrew Berglund at the University of Oregon for this work, results of which were published Oct. 12, 2009, in Proceedings of the National Academy of Sciences, early online edition.

Berglund said his group's experiments suggest that "a small-molecule strategy could lead to a drug for this disease." (Small molecules are generally easier to administer and target to specific areas than large molecules, such as proteins.)

About type 1 myotonic dystrophy

MMD1, which is characterized by skeletal muscle wasting and myotonia, also can involve cardiac, gastrointestinal, ocular and cognitive abnormalities.

In humans, MMD1 is caused by an expanded section of DNA in a gene on chromosome 19. The expanded DNA results in synthesis of longer-than-normal strands of RNA called "CUG repeats."  

In MMD1, the CUG repeats become trapped in the nuclei of muscle fibers, and protein molecules called MBNL in each nucleus become stuck to the CUG repeats. This entrapment of MBNL leads to “splicing errors” which affect the genetic recipe the cell follows to make protein molecules.

In MMD1, splicing errors lead to errors in the structure and location of chloride ion channels, which regulate passage of chloride into and out of the fibers. When the ion channels are abnormal, myotonia results.

Efforts are under way to disrupt the abnormal CUG-MBNL interactions and restore correct splicing. (See"Bright" Prospect.)

About these experiments

Researchers originally screened 26 compounds, two of which, pentamidine and neomycin B, counteracted some of the effects of the abnormal genetic instructions that cause MMD1. They then demonstrated in the lab and in mice with a disease resembling MMD1 that pentamidine was the more effective of the two.  

In studies conducted in a cell-based model with nearly 1,000 CUG repeats, pentamidine disrupted the complexes formed by the expanded repeats and the MBNL protein that becomes stuck to them. This allowed the MBNL protein to return to its proper location in the cell.

The researchers next looked at effects of the molecule in mice engineered to have 250 CUG repeats, resulting in a disease resembling MMD1. The mice were injected with either a low dose, twice daily, of pentamidine for five days, or a high dose, once daily, of the compound for seven days.

The investigators noted that pentamidine worked to inhibit MBNL-CUG interactions and partially rescued two splicing errors in the mice.

Berglund explained that a reversal of the myotonia did not occur "because only a partial reversal of the misregulated splicing occurs with pentamidine treatment in the mice." He added that, based on other studies, complete or nearly complete rescue of the misregulated splicing is required for the myotonia to be alleviated, and "the small therapeutic window of pentamidine [it's toxic at higher doses] doesn’t allow the full rescue of splicing."

Meaning for people with MMD1

Pentamidine has not been tested in people with MMD1. It is important to note, however, that it is already being used in humans to treat other conditions.

"Although pentamidine is not ready for use as a therapy for type 1 myotonic dystrophy, this work does demonstrate that a small-molecule strategy is a viable approach to this disease," Berglund said. "Almost all human diseases are currently treated with small molecules. Pentamidine is an exciting lead compound because it is relatively easy to chemically modify, and hopefully one of these modified compounds could lead to a safe, long-term treatment for type 1 myotonic dystrophy in the future."

One challenge is to decrease the toxicity of the molecule. Another, Berglund notes, "is to chemically modify pentamidine in such a way as to make it more specific for the CUG repeats while ensuring the compound is still able to easily reach the toxic CUG repeats within the cells of patients."
Get involved

If you or your child has type 1 or type 2 myotonic dystrophy, you're encouraged to join the National Registry of FSHD and MMD Patients and Family Members.

This registry, based at the University of Rochester, was developed to help people with myotonic dystrophy or facioscapulohumeral muscular dystrophy (FSHD) participate in research on their disease and help investigators connect with them.

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