In type 1 myotonic dystrophy (MMD1, or DM1), expansions of DNA on chromosome 19 known as CTG repeats are converted to expansions in RNA called CUG repeats, which are toxic to nerve and muscles cells in a variety of ways.
Several MDA-supported research teams are targeting the toxic CUG repeats, with the goal of either blocking their interaction with other cellular substances or destroying them entirely.
Disney and colleagues are using small molecules to target the MMD1-associated RNA. In experiments in cells in a culture dish that carried the MMD1 mutation, they found one of their experimental "H" compounds freed a protein from its entrapment in the CUG repeats and appeared to restore the cells to a normal, healthy state.
The investigators then studied some second-generation H compounds in mice with the MMD1-associated mutation and found that these compounds repaired an important aspect of cellular functioning without any apparent ill effects on the animals.
More testing for both safety and functional benefit will be conducted in mice before these compounds are tested in humans, Disney says.
Although he's optimistic about the new compounds, he notes, "Any drug that's going to be given to someone who has myotonic dystrophy type 1 is probably going to be given for the duration of their life. So we really have to make sure that these compounds, when they're exposed to animal subjects for a very long time, don't exhibit toxicity. You have to be very careful to do that before you do human testing."
Disney says a similar strategy is likely to be effective in type 2 myotonic dystrophy (MMD2, or DM2), a disease caused by a CCUG repeat expansion in a gene on chromosome 3.
Disney and colleagues have published the following additional papers on drug development for MMD1 and MMD2.