A method to specifically target disease-linked gene products is presented online this week in Nature Structural & Molecular Biology. The methodology used to target this disease could be used for gene silencing in other similarly caused disorders.
Myotonic dystrophy type 1 (DM1) is a multisystem disorder that affects skeletal and smooth muscle as well as other essential systems. DM1 is caused by expansion of a CTG repeat in the DM protein kinase (DMPK) gene that is present in the RNA message. It belongs to a group of disorders where the RNA, and not the protein, is responsible for the disease.
Mutant DMPK transcripts contain many expanded CUG repeats in the RNA and fold in such a way that they interact with proteins in the nucleus, to form stable RNA-protein aggregates. Strategies to treat the disease require repeated treatments with synthetic RNA molecules to counteract continuous expression of the toxic RNAs. To circumvent this limitation and trigger a long lasting effect, Denis Furling and colleagues have developed an optimized sequence to target the RNAs. These constructs cause specific degradation of pathogenic DMPK mRNAs without affecting wild type DMPK products.