Cugamycin, a small molecule compound targeting the disease-causing RNA repeats in people with myotonic dystrophy type 1 (DM1), showed promise in improving muscle defects — without evident side effects — in an early study using mouse and cell models, researchers report.
Their study, “Precise small-molecule cleavage of an r(CUG) repeat expansion in a myotonic dystrophy mouse model,” was published in PNAS.
DM1 is a neuromuscular disease caused by defects in the gene DMPK. In affected individuals, this gene contains too many repeats of a DNA sequence termed CTG.
A healthy person may carry between 5 to 34 of these repeats within the gene without any symptoms. But those who have the disease may have 50 to 5,000 CTG repeats, and typically between between 100 and 1,000.
In all cells, genes are transcribed into RNA molecules that serve as genetic blueprints for making proteins. In DM1 patients, the large expansions of CTG repeats found in DMPK lead to the production of very large and toxic RNAs.
The extra-long RNAs form clumps with other proteins that perturb a cell’s normal working. This is what leads to muscle damage and DM1 symptoms.
The disease has an autosomal dominant inheritance, meaning it is enough for a child to inherit a single copy of the mutated gene, from one parent, and develop DM1. That also means patients usually carry a functional copy of DMPK, inherited from the other parent.
Several approaches have been explored to tackle the disease-causing CTG expansions, including antisense oligonucleotides, CRISPR-based techniques, and RNA-targeting small molecules.
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In this study, researchers created an RNA-targeting compound — named cugamycin — that specifically recognizes the structure of the faulty RNAs, cutting them down.
Cugamycin consists on an RNA-binding molecule attached to a drug called bleomycin, which is the element with DNA-cutting activity.
An important feature is its ability to avoid off-targets, leaving healthy RNAs intact and free to perform normal functions — like protein production — inside cells.
In mouse models of DM1, as well as in cultures of patient-derived muscle fibers called myotubes, the molecule succeeded in clearing toxic RNAs while leaving normal RNAs unharmed.
“Analysis of the tissue from a pre-clinical disease model showed more than 98 percent of the disease defects are improved, with no detectable off-targets,” Matthew Disney, PhD, senior author of the study and a professor at Scripps Research Institute, said in a press release.
Compared to untreated mice, treatment with 10 mg/kg of cugamycin cut to half the frequency of myotonic discharges (moments when the muscle has difficulty in relaxing).
“A key next question will be to evaluate the effectiveness of our compound over a longer period of time,” said Alicia Angelbello, the study’s lead author and a graduate student at Scripps Research.
Results also suggest this approach can be used to not only treat myotonic dystrophy type 1, but is “likely applicable to many RNA-mediated diseases,” the study concluded.
“These studies demonstrate that small molecules can be designed to selectively cleave RNAs in a human disease model and improve phenotype,” the researchers wrote.
“Matt Disney is super-committed to making a treatment for this disease,” said Molly White, chief executive officer of the Myotonic Dystrophy Foundation. “We’re thrilled at the progress he is making.” The foundation is a long-standing supporter of Disney and his research.
DM1 is the most common muscular dystrophy of adults.