Locked nucleic acid

The linear strategy of synthesis was first detailed in the works of Obika et al.[7] In this approach, uridine (or any readily available RNA nucleoside) can be used as the starting material.

[10] The addition of different moieties has remained a possibility with the maintenance of key physicochemical properties like the high affinity and specificity evident in the originally synthesized LNA.

These modified oligonucleotides, like their DNAzyme relatives, are generally endonucleases that bind to specific RNA target sequences and cleave the phosphodiester bond that exists between the nucleotides.

Studies concluded that LNA toxicity is generally independent of oligonucleotide sequence, and displays a preferential safety profile for translatable therapeutic applications.

A locked nucleic acid phosphorothioate antisense molecule, termed SPC2996, has been developed to target the mRNA coding for Bcl-2 oncoprotein, a protein that inhibits apoptosis in chronic lymphocytic leukemia cells (CLL).

Phase I and II clinical trials demonstrated a dose dependent reduction in circulating CLL cells in approximately 30% of the sample population, suggesting further investigation into SPC2996.

[16] LNA has also been applied to Miravirsen, an experimental therapeutic intended for the treatment of Hepatitis C, constituting a 15-nucleotide phosphorothioate sequence with binding specificity for MiR-122 (a miRNA expressed in hepatocytes).