Thursday, May 17, 2007

A Framework for Progressing the Delivery of RNAi Therapeutics

The delivery of RNAi to the desired target organ is perceived by many to be the main hurdle before RNAi Therapeutics can have a universal impact on treating diseases. Arguably today already, it probably is possible to treat dozens of diseases for the eye and lung alone with current siRNA delivery methods. Furthermore, it is possible to efficiently knock down genes in the liver of primates, either with siRNAs formulations or viral gene therapy vectors. This is because the liver is the first pass organ for most drugs and highly vascularised thereby facilitating drug uptake.

The liver, however, demonstrates already some of the challenges we are facing. In the case of viral vectors, immunogenicity issues need to be addressed to make sure that immune responses against the vector will not abolish long-term gene knockdown. This is being addressed with efforts such as identifying novel serotypes or modifying pre-exising ones such as in the AAV field, but any of these solutions have yet to undergo testing in humans. For non-viral siRNA delivery, the main challenge at the moment is to get highly efficient gene knockdown without causing liver damage. It should be noted that limited liver damage is associated with a number of drugs on the market, however the degree of the damage needs to be tightly monitored. Needless to say, as with any drug, there is always a risk-benefit to consider. Alnylam published last year a study in Nature in which they show highly potent gene knockdown in primate liver. That in itself is a major achievement as only 2 years ago systemic delivery in humans was thought to be far on the horizon, and now it may happen much sooner. However, it was reported in the same study that there was a dose-dependent elevation of liver enzymes associated with the liposomally delivered siRNAs, in some cases quite high. Having established effective gene knockdown in primate liver, I would now expect the teams at Alnylam, Tekmira, Protiva, and Merck/Sirna to work on modifications of the liposomal delivery strategy that marries efficacy with little to no delivery-related side-effects

Beyond the liver, the reticuloendothelial system, kidney, intestines, and cancer, are probably next on the list of organs being targeted by systemic delivery. I expect more varied approaches to be taken to reach these organs, especially the use of targeting strategies such as adding cell-type specific targeting agents such as antibodies, peptides, or RNA-aptamers to a core delivery vehicle. This is an area where I see innovation particularly coming from the academic arena due to their freedom to explore. As a corporate strategy, however, I would be cautious in moving poorly characterised delivery strategies into the clinic, and put emphasis on further understanding and optimising promising technologies that exist today, such as the lipid-based technologies mentioned above. With scientists and funders working on all these fronts, it should be possible to gradually widen the scope for RNAi Therapeutics in a well-managed manner. From a commercial perspective, there are enough targets around now to focus on for the credible players in the field. I should add, however, that for orphan diseases or terminal diseases, more innovative strategies should definitely be considered for the clinic today.

Finally, I would like to appeal to all those involved in legal proceedings about who owns certain IPs in the delivery area. Please stop and realise that this is not helping anybody here, except of course for certain lawyers. It should be possible to set aside bruised egos and reach agreements with which everybody can live with that contributed to the development of a promising technology such as the liposomal delivery of siRNAs to mention just one example. Challenges such as liver toxicities associated with some of the liposomal vehicles are best solved when the scientists that co-developed and understand it best have access to.

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By Dirk Haussecker. All rights reserved.

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