Finding the keys to the world of gene silencing

These are exciting times in medicine: the era of gene-targeting drugs has arrived, promising new standards in safety, selectivity and rational drug design. Antisense oligonucleotides are the best known examples of gene-targeting therapeutic agents.

They are also the most clinically advanced, with one drug, Ciba-Geigy's Vitravene, already in use. RNA interference (RNAi and siRNA) is another gene targeting approach grabbing the headlines. How do these two technologies compare? How can we sort the hype from real hopes for new disease therapies? How close are these technologies to the clinic?

There is no doubt that at the moment, RNAi is capturing the imagination of the biotech community, as the first antisense oligonucleotides did over 10 years ago. The reality is that the discovery of 'small interfering RNAs' (siRNAs) has provided scientists with an effective new laboratory tool to identify the functions of genes and proteins, and to assist in the validation of new gene targets for drug and vaccine discovery.

Application of siRNA is currently limited to the discovery and validation of new candidate therapeutic targets, whilst the primary focus of antisense-based companies is the creation of human medicines themselves.

In addition to Vitravene, which is used in the treatment of a virally-induced eye inflammation of immunocompromised patients, more than 20 antisense compounds are currently in various phases of clinical trials, including three at the most advanced stage, Phase III.

As is the case for the development of any new drug or therapeutic treatment, antisense technology has followed a long and complex path to arrive at this stage of maturity, and along the way many significant challenges have been addressed. Early researchers faced initial setbacks related to stability, toxicity, tissue distribution and mode of delivery, all of which have been largely overcome with the advent of second generation proprietary chemistry in this second decade of antisense R&D.

Since the early 1990s, antisense technology has demonstrated the potential to create highly targeted drugs which prevent the appearance of a disease protein instead of trying to inactivate an existing protein.

On the other hand, siRNAs are still in the earliest stages of development for therapeutic use in humans.

As recently as October 2003, a paper in the Lancet posed the question of whether RNAi could realistically be exploited for therapy.

Interesting laboratory findings were cited, but as the authors conceded, "The ability to efficiently and stably produce and deliver sufficient amounts of siRNA to the proper target tissues requires refinement before this new technology can be tried clinically." Indeed many of the currently proposed therapeutic applications of RNAi envisage delivery strategies that have much in common with gene therapy. These approaches involve the use of plasmids or synthetic virus constructs to induce the expression of siRNA within the target cell. On the other hand, antisense drugs are delivered like conventional drugs: by injection, inhalation, topically, or in future, orally. The process of optimising delivery, stability and specificity is now largely complete for antisense therapeutics, following two decades of technology development and thousands of peer-reviewed scientific publications. In other words, antisense therapeutic technology has a 10 year jump on RNAi.

The progress from laboratory tool to human medicine is long and complicated. While RNAi-based technology has deservedly raised interest and excitement as a laboratory tool for exploring gene function, there is still some way to go before it can be considered for human use.

Antisense could be regarded as the third wave of drug development. The first wave started with small molecules in the 19th century and is exemplified today by drugs like aspirin and penicillin. The second wave appeared early last century and consists of therapies based on purified proteins (for example insulin, 1922) and antibodies, both of which benefited from the convergent new technologies of genetic engineering and monoclonal antibodies (1970s). These therapies are often referred to as 'biologicals'. In the third wave of therapeutic development, antisense medicines are designed with unprecedented selectivity and specificity, capitalising on the extensive knowledge of human gene sequences that resulted from recombinant DNA technologies and the human genome project.

Due to advanced scientific problem solving, we now know how to apply antisense technology to human therapeutics. With the significant number of clinical trials ongoing, antisense therapeutics are poised to make an impact in human medicine. Meanwhile, investigations of the potential of siRNAs as therapeutic agents are just embarking on the journey to clinical relevance.

Dr Christopher Wraight is Research Director at Antisense Therapeutics - a biopharmaceutical company engaged in drug discovery and development based on antisense technology. The company has several antisense drug development projects at various stages of development. The two most advanced of these are drugs against multiple sclerosis (ATL1102) and psoriasis (ATL1101), two conditions for which there are large, unmet needs for effective therapies. Dr Wraight is a Biochemist and is internationally recognised for his work in antisense delivery and gene silencing, particularly in the skin.