RNA interference - moving from lab to clinic

A collaboration between Cenix BioScience of Germany and the USA's Ambion has been formed to co-develop and market the first commercially-available, human genome-wide library of small interfering RNA sequences. RNA interference is emerging as a potent new tool for identifying the function of genes, with utility both in basic research and drug discovery.

Christophe Echeverri, Cenix' chief executive, chief scientific officer and lead founder, said: "we expect the discovery of new drug targets via genome-wide RNAi screening in human cells to drive a very wide and fast-growing range of biomedical research for years to come."​

Under the terms of the collaboration, Cenix will design the siRNA reagents, with Ambion synthesising them for certification by the German firm. Once validated, Ambion will market libraries of siRNA sequences, starting with those that target specific pathways (for example, for kinases), gene families and individual genes, and eventually building up an entire genome-wide library.

The first products from the alliance are due to reach the market this year. Cenix would not be drawn on the commercial potential of these initial offerings, but a spokesperson told In-Pharmatechnologist.com​ that market research, conducted by Ambion, suggests that pharmaceutical companies may be prepared to pay "several million dollars" for non-exclusive access to a genome-wide product.

So why is the technology so compelling? RNAi allows the inactivation of target genes by using complementary double stranded RNA which binds to messenger RNA and prevents protein transcription.

It is a naturally-occurring defence against molecular parasites, discovered in 1998 , and offers high specificity with a level of potency and stability which is far superior to that achievable with other technologies, such as antisense or ribozymes.

Despite its early promise, RNAi was initially limited to use in lower organisms such as Caenorrhabditis elegans and Drosophila, as dsRNA sequences tended to cause immune responses in mammalian cells. This was solved by the development of short sequences, typically comprised of less than 30 base pairs, which can evade this immune response whilst effectively achieving gene silencing.

Cenix' director of discovery, Birte Soennichsen, told In-Pharmatechnologist.com​: "The challenge was that the short length of siRNAs makes it hard to find a sequence that can block large mammalian genes. Cenix has partially solved this problem, so that in 70 per cent-80 per cent of cases knockdown of the targeted gene can be achieved."​

As a result, RNAi has become the method of choice for a wide range of biomedical applications, in particular emerging as the best functional genomics screening method to identify and validate new drug targets. In so doing, RNAi is not only replacing antisense- and ribozyme-based paradigms for cell-based research, but now also offers the promise of a more time- and cost-efficient alternative to transgenic mouse knock-out strategies.

Moreover, the properties which make siRNA sequences so useful in basic research - their potency, stability and specificity - also make them attractive as potential therapeutics, according to Soennichsen.

Nevertheless, there are significant hurdles to overcome before an siRNA-based therapeutic can enter the clinic. The primary obstacle is delivery; mouse studies have shown that siRNA can be administered and achieve gene silencing in vivo​, although this requires near-continuous delivery or administration in very high volumes, which limits its clinical utility.

There are various approaches which may solve this problem. One possibility is that a vector could be used to achieve in vivo​ expression of the desired siRNA sequence, although Soennichsen cautioned that recent concern over the safety of viral vectors in gene therapy trials has dampened enthusiasm for this approach, at least in the near-term.

For the moment, Cenix is leaning towards improving delivery via modifications of the siRNA molecule, or packaging it using some form of drug delivery technology. Effective delivery solutions are probably one to two years away, she said.

In the meantime, the company has a number of collaborations with academia looking at the use of specific sequences as therapeutics, and Soennichsen is confident that interest from "big pharma" will come once proof-of-principle studies in mice are completed.