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Small Molecule Treatment for Muscular Dystrophy
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Myotonic dystrophy is the most common form of muscular dystrophy. It is a chronic, slowly progressing disease that results in muscle wasting, heart defects, and endocrine problems. Myotonic dystrophy is a genetic disorder, passed from parent to offspring in an autosomal dominant manner. An autosome is a normal chromosome in the human cell. A dominant allele, such as the one that causes myotonic dystrophy, only requires one copy to show an effect on the host. An person affected with myotonic dystrophy only needs on mutated copy of the gene to have disease. This also means that half of an affected person’s offspring are likely to inherit the disease from one parent.

The mutation that causes myotonic dystrophy involves an increased number of triplet repeats in a segment of DNA. The mutation involved in myotonic dystrophy causes RNA produced off the DNA to bind to a protein in the cell nucleus, called MBNL1, that is involved in RNA splicing. When RNA splicing is inhibited by the MBNL1 protein being bound, other proteins are not produced in sufficient amounts. This improper protein production results in the symptoms of myotonic dystrophy. There is no cure available for myotonic dystrophy. Treatment involves management of symptoms. Cardiovascular effects are the most important symptoms to treat, as they are responsible for the majority of deaths due to myotonic dystrophy.

Researchers from the University of Illinois recently developed a small molecule that is able to enter the cell nucleus and disrupt RNA binding to the MBNL1 protein. By breaking up this binding, MBNL1 protein is able to function normally and assist with alternative splicing of RNA. Normal levels of other proteins can then be produced in the cell. The molecule, which has not yet been named, is water-soluble, which allows it to easily enter the cell and nucleus. It is specific to the repetitive RNA sequence associated with myotonic dystrophy, so it would not bind to other RNA molecules and affect normal cellular functions. The researchers found that the molecule was able to break up the protein-RNA interactions in live cells, the first such study to show a molecule capable of this function. The researchers were able to view the clusters of RNA and MBNL1 protein breaking up with microscopy, and also measured increased MBNL1 protein activity in the cells after treatment. Amazingly, this began to occur within only a few hours after treatment, indicating a very rapid effect.

The next steps in studying this molecule would be fruit fly and mouse studies. Seeing the positive effect in living cells is an important start, but tissue culture cells do not accurately depict what happens in the entire body. Other cellular factors within the body may affect how the molecule is distributed and taken up by the cells. The route of administration must also be determined in an animal model. The molecule must be able to enter a large variety of cell types in order to be effective throughout the body. Certain routes of administration may result in the molecule being degraded by the host. The dosing must be studied to make sure enough of the molecule is available to the body’s cells, without causing negative reactions. The number and timing of dosages must also be determined in animal studies, as the cell studies did not indicate how long the molecule is able to function in vivo. Modifications may be needed to the molecule to help aid in proper distribution throughout the body. In addition, cell culture studies may not adequately demonstrate potential toxic effects of the molecule.

Indeed, moving from tissue culture studies of cells to human clinical trials is a long, arduous process. There are many factors that need to be determined before human studies can even be considered. As exciting as it is that a potential treatment of myotonic dystrophy may be available, there are still many years until the therapy could be available for human studies. However, finding a molecule that can directly stop the RNA-protein clusters that seem to cause myotonic dystrophy is an important first step. Even if the molecule being studied is not ultimately usable as a treatment for myotonic dystrophy, it can help future research leading to the development of a successful treatment, or even cure, for myotonic dystrophy.


References:

http://www.sciencedaily.com/releases/201...145107.htm

http://en.wikipedia.org/wiki/Myotonic_dystrophy
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