Duchenne muscular dystrophy (DMD) is a recessive X-linked neurodegenerative disorder caused by mutations in the dystrophin gene. A promising strategy to treat DMD is exon skipping using antisense oligonucleotides (AONs), but approaches so far have been limited by poor tissue uptake. Now, Goyenvalle et al. demonstrate that a tricyclo-DNA (tcDNA)-AON rescues dystrophin expression and function in all affected tissues in mouse models of DMD.

Exon skipping using AONs coaxes the cell's transcriptional machinery to skip over a targeted exon, to restore an open reading frame and allow expression of a truncated but functional protein. However, in DMD, recent clinical trials testing either 2′-O-methyl-modified oligoribonucleotides (2′ OMes) or phosphorodiamidate morpholino oligomers (PMOs) have failed to show marked clinical benefit, probably owing to insufficient dystrophin rescue. Goyenvalle and colleagues therefore set out to investigate the therapeutic potential of a new DNA analogue, tcDNA—a conformationally constrained oligonucleotide analogue that, compared to natural DNA, has three additional carbon atoms between C5′ and C3′ that result in improved pharmacological properties.