Controlling RNA Expression has wide potential in therapeutics.Classical antisense has since 1978 been used as a single stranded strategy for RNA inhibition,but the clinical successes has so far been limited.One reason for this is a combination of low efficacy and too high toxicity of the previous generations of antisense oligonucleotides.With the discovery of RNAi/siRNA a new double stranded strategy was introduced for RNA inhibition.However,the high therapeutic prospect of siRNA s that initially was based on in vitro observations has turned out to be more challenging to realise.The main obstacles for siRNA therapeutics are effective intracellular delivery of the large double stranded siRNA s,and a satisfactory reduction of the off-target effects that often are associated with siRNA silencing mechanisms.These obstacles are only partially resolved.An important property for potent RNA targeting is a high binding affinity of the inhibiting oligonucleotide.When LNA (Locked Nucleic Acid) was invented in 1997 it was demonstrated that oligonucleotides comprising LNA-nucleotides (defined as LNA) exhibited unprecedented high RNA binding affinity.It has now been demonstrated in numerous papers that the high affinity of LNA translates into high potency in RNA silencing.