Possible help in fight against muscle-wasting disease

November 06, 2009

A compound already used to treat pneumonia could become a new therapy for an inherited muscular wasting disease, according to researchers at the University of Oregon and the University of Rochester School of Medicine and Dentistry in New York.

The five-member team reports that pentamidine, when tested in genetically altered mice, counters genetic splicing defects in RNA that lead to type 1 myotonic dystrophy -- one of nine types of muscular dystrophy -- also known as DM1 and Steinart's disease.

The compound was among 26 tested in the UO lab of chemist J. Andrew Berglund. Pentamidine carries approval of the U.S. Food and Drug Administration for treating a severe type of pneumonia in people with weakened immune systems, as well as leishmaniasis, sleeping sickness and some yeast infections. However, levels used successfully in the experiments would be toxic in humans, Berglund said.

With modifications, he added, pentamidine could be adapted to reverse RNA splicing defects that drive type 1 myotonic dystrophy. "The fact that a very small library of compounds yielded a molecule capable of reversing the splicing defects associated with DM1 in both cell and mouse DM1 models suggests that a small molecule strategy could lead to a drug for this disease," he said.

The experiments -- done by former UO doctoral student M. Bryan Warf and Catherine M. Matthys, who has since graduated from the UO, and Rochester's postdoctoral researcher Masayuki Nakamori -- identified pentamidine and neomycin B as compounds that worked against abnormal genetic instructions. Pentamidine, however, was found to be the most effective in the mice. Berglund, a member of the UO Institute of Molecular Biology, and Dr. Charles A. Thornton, a neurologist at Rochester, were co-authors of the study.

The research -- supported primarily by grants from the National Institutes of Health and the Muscular Dystrophy Association -- was published in the Nov. 3 issue of the journal Proceedings of the National Academy of Sciences. In a separate commentary in PNAS, Thomas A. Cooper of the Baylor College of Medicine in Houston hailed the findings, noting that the compound is the first to show such promise of reversing splicing defects. Cooper also noted that such a therapeutic approach is attractive because of the potential benefits to multiple organs affected by the disease.

DM1 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 sequences, or repeats, of the chemicals cytosine, uracil and guanine. These abnormal pieces get trapped in the nuclei of muscle fibers, and protein molecules called MBNL in each nucleus become stuck to the CUG repeats. This leads to errors in the splicing process in which important proteins are made incorrectly or not at all. In turn, disruptions in muscle fibers cascades into changes in ion channels that impacts the ability of muscles to relax after use.

Researchers found that pentamidine disrupted the complexes formed by the expanded repeats and the MBNL protein that becomes stuck to them, allowing the protein to return to its proper location in the cell. The compound also inhibited interactions of MBNL with the cytosine-uracil-guanine repeats and partially rescued two splicing errors in the mice.

Pentamidine has not been yet tested in people with DM1, Berglund cautioned, but its FDA approval for other uses is important.

"Although pentamidine is not ready for use as a therapy for DM1, 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 DM1 in the future."
-end-
The University of Rochester's medical school maintains the National Registry of FSHD and MMD Patients and Family Members. The registry is designed to help people with myotonic dystrophy or facioscapulohumeral muscular dystrophy participate in research on their disease and help investigators connect with them.

About the University of Oregon

The University of Oregon is a world-class teaching and research institution and Oregon's flagship public university. The UO is a member of the Association of American Universities (AAU), an organization made up of the 62 leading public and private research institutions in the United States and Canada. The UO is one of only two AAU members in the Pacific Northwest.

Source: Andy Berglund, associate professor of chemistry, 541-346-5097, aberglund@molbio.uoregon.edu

Links:

Berglund Web site:
http://www.molbio.uoregon.edu/facres/berglund.html

Institute of Molecular Biology:
http://www.molbio.uoregon.edu/index.html

UO chemistry department:
http://www.uoregon.edu/~chem/

Muscular Dystrophy Association:
http://www.mda.org/

National Registry of FSHD and MMD Patients and Family Members:
http://www.urmc.rochester.edu/neurology/nih-registry/

Video comments from Berglund:
http://www.youtube.com/v/f5wLuMZnpf8

University of Oregon

Related Muscular Dystrophy Articles from Brightsurf:

Using CRISPR to find muscular dystrophy treatments
A study from Boston Children's Hospital used CRISPR-Cas9 to better understand facioscapulohumeral muscular dystrophy (FSHD) and explore potential treatments by systematically deleting every gene in the genome.

Duchenne muscular dystrophy diagnosis improved by simple accelerometers
Testing for Duchenne muscular dystrophy can require specialized equipment, invasive procedures and high expense, but measuring changes in muscle function and identifying compensatory walking gait could lead to earlier detection.

New therapy targets cause of adult-onset muscular dystrophy
The compound designed at Scripps Research, called Cugamycin, works by recognizing toxic RNA repeats and destroying the garbled gene transcript.

Gene therapy cassettes improved for muscular dystrophy
Experimental gene therapy cassettes for Duchenne muscular dystrophy have been modified to deliver better performance.

Discovery points to innovative new way to treat Duchenne muscular dystrophy
Researchers at The Ottawa Hospital and the University of Ottawa have discovered a new way to treat the loss of muscle function caused by Duchenne muscular dystrophy in animal models of the disease.

Extracellular RNA in urine may provide useful biomarkers for muscular dystrophy
Massachusetts General Hospital researchers have found that extracellular RNA in urine may be a source of biomarkers for the two most common forms of muscular dystrophy, noninvasively providing information about whether therapeutic drugs are having the desired effects on a molecular level.

Tamoxifen and raloxifene slow down the progression of muscular dystrophy
Steroids are currently the only available treatment to reduce the repetitive cycles of inflammation and disease progression associated with functional deterioration in patients with muscular dystrophy (MD).

Designed proteins to treat muscular dystrophy
The cell scaffolding holds muscle fibers together and protects them from damage.

Gene-editing alternative corrects Duchenne muscular dystrophy
Using the new gene-editing enzyme CRISPR-Cpf1, researchers at UT Southwestern Medical Center have successfully corrected Duchenne muscular dystrophy in human cells and mice in the lab.

GW researcher finds genetic cause of new type of muscular dystrophy
George Washington University & St. George's University of London research, published in The American Journal of Human Genetics, outlines a newly discovered genetic mutation associated with short stature, muscle weakness, intellectual disability, and cataracts, leading researchers to believe this is a new type of congenital muscular dystrophy.

Read More: Muscular Dystrophy News and Muscular Dystrophy Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.