What is antisense therapy?

The human genome comprises an estimated 25,000 different genes, each of which directs the synthesis of a unique RNA (a single-stranded copy of the gene), which, in turn, directs the synthesis of a unique protein. Antisense drugs are short synthetic pieces of DNA (called oligonucleotides) that are rationally designed on the basis of the Watson-Crick base pairing rules to specifically bind to a unique RNA molecule and inhibit its ability to synthesize its encoded protein. Thus, antisense drugs combat disease by preventing protein synthesis rather than inhibiting the proteins directly, as most small molecule and antibody drugs do. (Figure 2)

To be an effective antisense drug, the oligonucleotide needs to have a number of characteristics that allow it to reach its RNA target in the cell intact, in sufficient quantity and with sufficient affinity to cause a pharmacologically meaningful response. Developing antisense oligonucleotides with such characteristics has proven a significant challenge for more than two decades. With the invention of LNA-based oligonucleotides, however, such antisense molecules have now become a reality.


Figure 2: High affinity binding of LNA-oligonucleotide to target mRNA activates RNAse H and degrades mRNA reducing target protein levels