**Table 2.**

*Chemical modification characteristics.*

of the ribose [46]. LNA modifications improve significantly the ASO hybridization affinity towards mRNA target, due to the important increase in the thermal stability of the DNA/RNA heteroduplexes [47]. In addition, LNAs avoid nuclease degradation. As their ribose 2'-O position are modified, LNAs are not recruiting RNase H [48]. Nevertheless LNA nucleotides can be freely incorporated at the ends of RNA and DNA sequences to form chimeric oligonucleotides resulting in restoration of RNase H-mediated cleavage of mRNA. It has been shown that the chimeric LNA/ DNA/LNA gapmer with seven to 10 phosphorothioate-modified DNA central gaps flanked by three to four LNA nucleotides on both 5′-end and 3'ends induces efficient mRNA cleavage, because of their high target affinity and nuclease resistance [29]. In the first *in vivo* study reported, the LNA ASOs appeared to be nontoxic in the optimal dosage. Therefore, full LNA and gapmers LNA·DNA·LNA ASOs seem to offer an attractive set of properties, such as potent biological activity and apparent lack of acute toxicity, making it a promising antisense agents [49–51]. **Table 2** recapitulates the chemical modifications characteristics.

Despite the large number of molecules being evaluated in the clinical trials, the clinical progress of ASOs had to face many challenges; indeed, poor pharmacokinetics [52], poor cell membrane permeation [53], and off-target effects [27]. Last decade, the development of oligonucleotide delivery through lipid or polymer systems has improved the cellular uptake and the pharmacokinetic behavior [54].
