DM1 is the most common form of adult-onset muscular dystrophy. “This finding opens a new avenue for a therapeutic strategy for this disease,” said Prof. Andrew Berglund, Ph.D. “This is the first evidence that specifically inhibiting transcription can be effective in knocking down the toxic material that causes the disease.”
In myotonic dystrophy and other related neurological disorders, the symptoms stem from repeated individual nucleotides in the RNA in muscle tissue cells that can build up over time. These repeats, called CTG expansions in myotonic dystrophy type 1, become “toxic” when transcribed from DNA. The expansions disrupt the RNA binding proteins responsible for splicing, the “editing” needed so that the RNA can create appropriate proteins that allow muscles to function properly.
Highlights ~d Actinomycin D (ActD) reduced toxic CUG RNA levels in DM1cell and mouse models ~d ActD rescued DM1-associated mis-splicing events in mice ~d RNA sequencing revealed that low doses of ActD did not globally inhibit transcription ~d CUG reduction and splicing rescue occurred within approved ActD therapeutic ranges
He and colleagues looked at actinomycin D, an antibiotic currently used to treat certain types of cancers by preventing cancer cells from transcribing, or copying, essential cancer information to new cells. Because the anticancer compound works by binding to troublesome expansions in DNA, the researchers decided to test whether it would work in cells and a mouse model of myotonic dystrophy type 1.
They found that very small concentrations of actinomycin D resulted in almost complete correction of the mis-splicing. They also tested to see if the drug was inhibiting production of normal RNAs in the cells, and found that it altered <5% of normal RNA sequences. “There was a significant level of specificity for the toxic RNA,” said Berglund, a member of the UF Center for NeuroGenetics. “Actinomycin D can reduce the toxic RNA, and also inhibit it from forming.”
While this drug shows promise, Berglund said that it might not end up being the compound used in eventual clinical trials. However, the research findings do indicate that this is an approach that needs to be looked at, he said. The next steps in the research include screening for other compounds with similar activities to actinomycin D that might be equally or more effective, exploring the possibility of modifying actinomycin D to increase its effectiveness and using the antibiotic with other inherited muscular dystrophies to see if it shows promise for those diseases.
https://ufhealth.org/news/2015/cancer-drug-shows-promise-reducing-toxic-genetic-material-myotonic-dystrophy
http://www.cell.com/cell-reports/pdf/S2211-1247(15)01328-5.pdf
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