Defects in mRNA 3′ end formation have been described to alter transcription termination, transport of the mRNA from the nucleus to the cytoplasm, stability of the mRNA and translation efficiency. Therefore, inhibition of polyadenylation may lead to gene silencing. Herein, Facioscapulohumeral Dystrophy (FSHD) was used as a model to determine whether or not targeting key 3’end elements involved in mRNA processing using antisense oligonucleotide drugs can be used as a strategy for gene silencing within a potentially therapeutic context. FSHD is a gain-of-function disease characterized by the aberrant expression of the DUX4 transcription factor leading to altered pathogenic deregulation of multiple genes in muscles. The authors demonstrate that targeting either the mRNA polyadenylation signal and/ or cleavage site is an efficient strategy to downregulate DUX4 expression and to decrease the abnormally high pathological expression of genes downstream of DUX4. They conclude that targeting key functional 3’end elements involved in pre-mRNA to mRNA maturation with antisense drugs can lead to efficient gene silencing and is thus a potentially effective therapeutic strategy for at least FSHD. Moreover, polyadenylation is a crucial step in the maturation of almost all eukaryotic mRNAs, and thus all mRNAs are virtually eligible for this antisense-mediated knockdown strategy.
Marsollier AC, Ciszewski L, Mariot V, et al. Antisense targeting of 3’end elements involved in DUX4 mRNA processing is an efficient therapeutic strategy for Facioscapulohumeral Dystrophy: a new gene silencing approach. Hum Mol Genet. 2016 Jan 19. pii: ddw015. [Epub ahead of print]