mechanism of action

What is an LNA-based drug?

LNA is a modification of RNA that contains an oxy-methylene bridge between the 2' and 4' carbons in the ribose ring. This bridge creates a bi-cyclic structure that locks the conformation of the ribose and is the key to the high stability and affinity of LNA to its complementary nucleotide sequence.

The most important features of LNA antisense oligonucleotides commonly observed across molecules of this class include:

  • excellent specificity, providing optimal targeting
  • increased affinity to targets providing improved potency in-vivo in many different tissues
  • strong pharmacology upon systemic delivery without any need for complicated delivery vehicles
  • ability to target desired tissue through the use of LNA drug conjugates (LNADC)
  • well-tolerated with predictable toxicology at doses that far exceeds relevant clinical doses
  • potential for oral delivery
  • scalable and cost-effective manufacturing

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 with past technologies. With the invention of Santaris’ LNA-based oligonucleotides, however, such antisense molecules have now become a reality.

Antisense MOA - Using antisense inhibition, high affinity binding of LNA-based oligonucleotides target mRNA, activating RNAse H and degrading mRNA, thereby reducing target protein levels

microRNA MOA - LNA-based oligonucleotide binds to the miRNA and prevents its activity inside the cell. This typically results in an increase in the miRNA's target protein expression