Locked nucleic acid oligonucleotides towards clinical applications

Nucleic acid–based therapeutic technologies (Figure 9.1) have significantly advanced in the past two decades toward the treatment of many diseases. The first such drug to enter clinic was vitravene®, an antisense oligonucleotide for the treatment of cytomegalovirus retinitis [1]. Later, research on aptamers led to the marketing of macugen®, an inhibitor of vascular endothelial growth factor (VEGF) for the treatment of age related macular degeneration (AMD) [2]. Nucleic acid–based therapeutic approaches mainly include antisense [3,4], ribozymes [4], small interfering RNA (siRNA) [4–6], microRNA (miRNA) [7–10] targeting and aptamers [11–15]. Oligonucleotides composed of naturally occurring DNA or RNA nucleotides pose some limitations because of their poor RNA binding affinity, low degree of nuclease resistance, and low bioavilability. To overcome these limitations, chemically modified nucleic acids have been introduced, among which locked nucleic acid (LNA) [16–20] proved to be unique and is now used extensively for various applications in chemical biology [21–23]