New research from a University of Minnesota research collaboration identifies a copolymer well suited to stabilizing muscle cell membranes in a model of Duchenne muscular dystrophy (DMD).
Poloxamer 188 (P188) is a block copolymer membrane stabilizer. In a new paper published in Molecular Therapy-Methods & Clinical Development, researchers showed this stabilizer works well to protect the dystrophic skeletal muscles.
Duchenne muscular dystrophy (DMD) is a genetic disorder impacting boys almost exclusively. It carries a devastating diagnosis, with progressive muscle degeneration. Caused by a lack of dystrophin, a protein necessary for keeping muscles intact, DMD is usually first noticed around age 3. Life expectancy has historically been only through the late teens, but developments in research and treatment have shown promise with some men surviving slightly longer.
“The membrane is the cell’s first and last line of defense, particularly in diseases like DMD,” said Joseph Metzger, Ph.D., professor and head of the Department of Integrative Biology and Physiology and part of the research team on this project. “Like missing shingles on the roof to a house, if the cell membrane is damaged, your cells won’t die off immediately but they will need repair. Without protection, continued stress on the dystrophic muscle cells will cause increasing damage and ultimately cell death.”
Looking to target the cell membranes, Metzger and his colleagues teamed up with researchers from the College of Science and Engineering. Frank Bates, Sc.D., Regents Professor in the Department of Chemical Engineering and Materials Science, is an expert on polymers and chemical modification. He was a natural fit for the collaboration.
“Collaborations and partnerships in science are remarkable roads to discovery. No science, no discovery, is done in isolation,” said Bates.
This particular project first looked at P188, and showed its use in protecting the myocardium in DMD mouse models. Researchers then wanted to assess its benefits to protect dystrophic skeletal muscle.
“The heart is a muscle. Limbs are muscle. But they don’t operate the same, they are not structured exactly the same,” said Metzger. “We wanted to find a way to apply the effective cardiac therapy to skeletal muscles.”
Turns out, method matters. Results of the research show a dramatic increase in effectiveness when P188 is delivered under the skin instead of in the blood or in the muscle directly. The reasons for this are not entirely clear, but may have root in the way P188 interacts with the muscle cell membrane.
Evelyne Houang is a Ph.D. candidate in the Department of Integrative Biology and Physiology
“Finding this therapeutic with its potential as a treatment was the most exciting aspect of this paper for me,” said Evelyne Houang, the first author on the paper. Houang is a Ph.D. candidate and researcher in the Metzger lab. “The next goal is to understand the structure-function relationship of this membrane stabilizer. How can we alter the chemical structure of P188 to make it even more effective?”
Continued investigation is ongoing, as part of a larger collaboration between Metzger, Bates, Houang, and several researchers of varied disciplines.
“When you’re looking at a problem, basic science can sometimes feel like going blindly into the darkness when you begin an investigation,” said Bates. “Collaborations like this one, with people addressing problems from many areas of expertise and interest, allow us to more quickly and efficiently find the light switch.”
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