What is Antisense Therapy?                         

Antisense therapy aims to tackle illness which can be traced back to a source that is encoded for by genetic information, namely abnormal or faulty proteins. The basic principle underlying the technology is to use an oligonucleotide (ASO) sequence, or sequence mimic, to interfere with the transfer of information from DNA to protein inside a cell. This is achievable because a DNA coding sequence, a gene on the ‘sense’ strand, must be transcribed (via its anti-sense strand) into RNA (specifically mRNA) before being translated into protein (the central dogma of molecular biology).

It is possible to design a short, highly specific, nucleotide sequence that is complementary to the single stranded target mRNA and binds tightly to it. Note that this approach is subtly different from the RNAi technique, which uses a double stranded RNA as the therapeutic molecule (for a comparison see here). After ASO-mRNA binding, one of several interference mechanisms can occur (further information see reviews here and here). The most commonly exploited mechanism results in destruction of the mRNA, as once bound to the ASO it enables recognition and action by RNA degradation enzymes, thereby ‘silencing’ the gene as it will not be translated into protein.

The extremely specific targeting of the desired protein that can be achieved makes it an excellent therapeutic approach, minimising risk of off-target activity producing unwanted side-effects and opening up almost any disease to treatment. However, as with all drug discovery projects, the target must be well validated and there are several obstacles to overcome in delivering the therapeutic agent – not least of which is the fact that cells are filled with enzymes that love to chew up loose DNA (exo and endo nucleases), which are sat ready to deactivate the carefully crafted oligonucleotide after it crosses the cell membrane; a challenge in itself! On top of this there is also a risk of generating an immunogenic response when mimicking natural nucleic acid structures.

Chemical modification of the oligonucleotide sequence can sidestep enzymatic degradation, a good example being changing the phosphodiester linkage to a phosphorothioate, which is utilised by antisense therapeutics already in the clinic. Modification is also needed to overcome difficulties in crossing the cell membrane, which is necessary for the drug to gain access to its target, and reduction of immunogenicity. As a result, this is an area of chemistry which is ripe for research, especially at Oxford, and has the potential to be a real showcase for the utility of synthetic organic chemistry in the 21st century. A comprehensive review on gene silencing technologies and getting them from the lab into the clinic was published in 2012.

How is it impacting the biotech world?

Antisense technology has the potential to benefit large numbers of patients across a range of illnesses, as its targeting of RNA makes it particularly suited to tackling viral infection, as well as rare genetic disorders, cancer, auto-immune and cardiovascular disease.

The advent of such a promising technology has spawned a new wave of biotech companies, with ISIS Pharmaceuticals at the forefront, already having approval for an antisense drug against cholesterol, and a strong pipeline of other prospects. Working in this field is not without risk however, as demonstrated by the 2012 bankruptcy filing of Genta, originally launched in the 1990s as a promising biotech company dedicated to the commercialisation of this technology.

On the other hand, there is huge reward for those who can find success with antisense, as evidenced by American biotech Celgene’s recent $710m acquisition of a promising antisense therapeutic against Crohn’s disease (a form of IBD). A deal of this size, and the emergence of other biotech firms like GeneSignalSarepta Therapeutics and Isarna Therapeutics, gives a strong indication of the commercial potential antisense technology now has and the fact that it is finally starting to make sense to the big players in the pharmaceutical industry.


Written by: Oliver Coleman, Editor-in-Chief