Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder characterized by myotonia, weakness, cardiac arrhythmias, diabetes and cognitive deficits. Patients carry an expansion of the CTG DNA repeat sequence in the DMPK gene. As a result, when the mutant gene is expressed, it yields a toxic messenger RNA molecule (a gain-of-function effect). In addition to the mutant DMPK gene patients carry a functional copy of the gene.
Antisense oligonucleotides (ASOs) are synthetic RNA-like fragments that can bind to a target RNA leading to a gene-specific knockdown effect. Â A potential strategy for treating DM1 is to ‘silence’ the mutant DMPK using antisense oligonucleotides designed to bind selectively to the mutant RNA and mark it for degradation (while leaving the product of the functional copy of the gene intact). Wheeler et al. report on the successful use of ASO to correct the physiological, histopathologic and transcriptomic features of the disease in a transgenic mouse model of DM1.
Targeting nuclear RNA for in vivo correction of myotonic dystrophy.Wheeler et al. Nature. 2012 Aug 2;488(7409):111-5. PMID: 22859208
posted by Yannis Trakadis, MD