Researchers at the University of Illinois have engineered a new small molecule to combat myotonic dystrophy type 1, the most common form of muscular dystrophy in adults. The molecule works by dissolving the abnormal protein-RNA clusters that cause the disease in living human cells.
There is no treatment available for the disease, which causes progressive weakness as muscles deteriorate over time for about 1 in every 8,000 people in North America.
Myotonic dystrophy type 1--also known as DM1--is caused by a mutation to one gene. In a healthy person, a small segment of the gene--a DNA sequence of CUG--is repeated a few times, but in someone with DM1, the sequence is repeated more than 50 times, or even up to thousands of times. The sequence is transcribed into RNA over and over, which binds to the protein MBNL1--essential for regulating protein balance in cells.
"These long sequences of CUG--which get longer as a patient ages--are toxic because they bind a protein called MBNL which is a regulator of a process called alternative splicing," UI chemistry professor Steven Zimmerman said to FierceBiotechResearch. Alternative splicing essentially regulates protein balance in cells.
In people with DM1, the repeating CUG causes MBNLI to migrate into the nucleus of the cell, causing an imbalance of proteins and leading to protein-RNA clumps. This is how the disease is formed.
The researchers, led by Zimmerman, discovered a small molecule that infiltrates the nucleus and binds to the RNA, liberating it to function normally. The molecule--which is designed to exclusively target the repeating RNA sequence--is water-soluble, so unlike larger molecules, it can cross the membrane into the cell. In lab cells, the researchers observed that the small molecule broke up the clusters in the cell nucleus and MBNL1 protein had increased its regulatory activity.
"The next step would be to see the level of toxicity in mice and whether it can improve the DM1 symptoms in mice," Zimmerman said. "If the compound is successful in mice, then we envision companies being very interested and the possibility of starting clinical trials."
- here's the press release