Locked nucleic acids (LNAs) are artificial nucleic acid analogs which contain a methylene bridge connecting the 2′-O with the 4′-C position in the furanose ring (Fig. 1a)20, 21. This modification makes them resistant to nucleases and increases affinity to complementary RNA sequences. The LNA chemistry has been used for gapmer AONs, single strand DNA oligonucleotides flanked by several LNA bases at the 5′ and 3′ ends22. Gapmer AONs bind targeted mRNAs and degrade them by activation of RNase H22. LNA/DNA mixmers (AONs composed of alternating LNA and DNA nucleotides) have been recently developed, which induce exon skipping in dystrophin mRNA (LNA-based splice-switching oligonucleotides) in vitro 23, or inhibit miRNA to protect the heart against pathological cardiac remodeling to improve the heart function (LNA-antimiR) in vivo 24. Miravirsen (AntimiR-122) is an LNA-antimiR that inhibits miR-122 to treat hepatitis C infection25, 26. MRG-106 (AntimiR-155) is another LNA-AntimiR and targets miR-155 for the therapy of cutaneous T cell lymphoma and mycosis fungoides26. The clinical trials of both LNA-antimiRs are currently ongoing26. One of the advantages of using LNA/DNA mixmers for treatment is that they have negatively charged backbones. This is expected to make delivery into cells more efficient than PMOs which are neutrally charged.Figure 1LNA structure and LNA/DNA mixmer sequences. (a) Chemical structures of RNA and phosphorothioated LNA. (b) LNA/DNA mixmer sequences targeting SMN2 intron 7. DNA base: G, A, T, C. LNA base (red): +G, +A, +T, +C. Phosphorothioated DNA base: G*, A*, T*, C*. Phosphorothioated LNA base (red): +G*, +A*, +T*, +C*.