Leap of faith

Like many technologies before it, therapeutics based on nucleic acids began with a good idea and a leap of faith. In the case of RNA inference (RNAi), the idea is simply to stop a specified gene product before it can create problems ñ just about as close to genetic manipulation as you can get without altering actual genes.

This idea came to life with a core of technology but it has taken years of discoveries and refinements and the introduction of enabling technologies to make RNAi part of the bench, much less the clinic.

RNAi was first discovered in Caenorhabditis elegans ñ a worm ñ nearly a decade ago and has been revolutionising gene-function analysis ever since. This discovery began the process by which scientists work with a known gene sequence and attempt to define its biological function by disrupting its activity in vivo.

Despite the variety of technologies aimed at RNAi, the actual feat of disrupting a specific gene's function was, for years, not possible because of the basic lack of genomic information. However, advances in gene sequencing have allowed various usages of available technology to select any gene and try to identify the gene, as well as to understand its specific function. From there, RNAi can be introduced, with dsRNA as the interfering agent.

Risky business
Increasing numbers of companies are entering the arena for RNAi/siRNA therapeutics development. To date, the technology has proved useful in validating drug targets and the determination of gene function, which leads to its potential in the therapeutics field. However, the technology is still young in terms of its therapeutic potential and fraught with the possibilities of developmental barriers.

Investment money is flowing into companies adopting this technology to the extent that at least one company, Ribozyme Pharmaceuticals (now Sirna Therapeutics), abandoned its original technological focus and name in favor of RNAi. However, not one siRNA compound is out of preclinical development and most are research-stage projects.

There remain many 'ifs' in siRNA research and development: 'if' everything goes smoothly; 'if' siRNA's pharmacokinetic properties are acceptable; 'if' siRNA's pharmacodynamic properties are acceptable; 'if' the toxicology profiles are acceptable; 'if' the compounds can be shown to be therapeutically effective.

However, if the product can be fast-tracked or given orphan drug status, it might be possible to have an RNAi drug on the market within seven to 10 years.

It is difficult, therefore, to determine the impact of RNAi on the field of nucleic acid-based therapeutics and pharmaceutical markets. One sure impact is that it is draining investment funds from other areas of development.

Big potential
As the hottest property in nucleic acid therapeutics, RNAi/siRNA stands to gain the most from the emergence of these therapeutics. In a recent analysis, Kalorama Information quantified the potential of these emerging nucleic acid therapeutics in the top disease targets and top world markets. The study revealed that the big risks may have enormous payoffs for innovators, investors and patients.

The world market for nucleic acid therapeutics is less than a few billion dollars. However, the market potential of these therapeutics is huge. Advances and discoveries in seemingly unrelated areas of biotech have a significant effect on what products and technologies will emerge as winners and losers.

The greatest market potential for these products is seen in the area of neurological diseases ($83bn), followed by cancer ($44bn) and autoimmune diseases ($42bn). Each of these represents only about 50 per cent of the potential for neurological disease treatments. Fourth in this progression is cardiovascular disease ($33bn), a major cause of death in all of the seven major world healthcare markets. Lastly, diabetes ($6bn) and rheumatoid arthritis ($3bn) round out the total.

In many areas, the potential of RNAi therapeutics really represents the vulnerability of the existing product base. This means that the nucleic acid-based products will replace current therapeutics to a large extent. This is especially true for areas where current pharmaceuticals have significant side effects, such as cancer therapy, or where current pharmaceutical treatments are of doubtful benefit, such as congestive heart failure.

However, there are areas in which nucleic acid-based pharmaceuticals will provide incremental growth. These will be in areas where there are largely no effective treatments (neurotherapeutics) or where it has been difficult to develop necessary products (vaccines). In these areas, RNAi may be expected to expand the world pharmaceutical markets greatly.

The future
Given the business and clinical promise of RNAi technologies and the current level of investment, the immediate future looks bright for developers. Kalorama anticipates a relatively stable competitive picture over the next few years, with the mad gold rush over for now. Specialty companies who have the lion's share of intellectual property and research expertise will predominate, with big pharma companies sitting back and assessing partnership and acquisition potential based on results.

The next five to 10 years will tell the tale, as RNAi/siRNA leave the sheltered world of the bench scientist and enter the dangers of clinical development. Great rewards await, ifÖ

The Author
Steven Heffner is editor for Kalorama Information

Further reading
Nucleic Acid-Based Therapeutics: World Markets, Developments and Applications