Antisense Oligonucleotides

Antisense Oligonucleotides

Underpinning Science

Antisense technology is a tool that is used for the inhibition (silencing) of gene expression. The principle behind it is that an antisense nucleic acid sequence base pairs with its complementary sense RNA strand and prevents it from being translated into a protein. Gene silencing is widespread in nature and was first used as a tool to inhibit genes in mammalian cells in 2001. Bacteria themselves use natural antisense mechanisms and may be uniquely amenable to antisense control. To date, six antisense oligonucleotide (ASO) drugs have received market authorization by regulatory authorities for indications other than bacterial infections, and at least four drugs are in the latter stages of development/market.

ASOs as anti-bacterials have been largely unexplored primarily due to the poor uptake efficiency of such molecules by bacteria. Efficient delivery of ASOs to the site of infection and into bacteria at efficacious concentration has been a major obstacle, which has greatly hampered their clinical application to date (Xu et al 2018). A single versatile and safe system suitable for efficient delivery of ASOs would be of huge health and consequently economic benefit.

Compared to traditional antibiotics, ASOs have immense potential to control the spread of resistant microbes due to their high specificity of action, little risk to human gene expression, plus a predictable and straightforward design and synthesis. Unlike traditional antibiotics that usually target a universal cellular process and kill bacteria with little selectivity, ASOs target a specific DNA sequence in bacteria. For instance, the ASO may target E. coli without unintended effects on commensal bacteria or other strains such as Pseudomonas, Acinetobacter baumannii or Klebsiella. It does this by targeting a gene through sequence complementation i.e. via Watson-Crick base pairing.

There are conceptual advantages to bacterial cell targeted RNA therapeutics, including a sequence-dependent approach that allows for rapid and rational design to multiple specific molecular targets (Henry & Stewart 2018). This reduces drug discovery time and provides flexibility to drug development.

Similar to the liver targeting technologies of the leading public RNAi companies (Ionis, Discerna, Alnylam), Pedanius has developed a proprietary delivery technology for a fast-facilitated delivery of ASOs exclusively to bacterial cells. This ligand-mediated technology is highly differentiated from traditional cell penetrating peptide (CPP) approaches in that it only enters bacteria (not eukaryotes) and does not “flip-flop” in and out of cells like CPPs. When coupled with highly bacteria specific ASOs, this confers an exquisite degree of selectivity.