Monday, June 23, 2008

Developing Multi-Functional RNAi Therapeutics

The great attraction of developing therapeutics based on RNAi is its inherent specificity and applicability to virtually any gene for the rational design of drugs. The specificity of gene silencing is not just a theory, but very powerfully attested by the many successes of applying RNAi even to genome-wide screens to uncover gene function (and also more targets for RNAi). Delivery of the RNAi inducer to the cells of interest would further add to such specificity and consequently safety.

However, as has long been known, certain nucleic acids elicit immune responses, and siRNAs are no exception to this. Although this does not apply to appropriately designed and vetted siRNAs, when it does, it may well interfere with the interpretation and predictability of the knockdown phenotype. However, instead of describing once again methods whereby such responses can be avoided and phenotypes more consistently obtained (siRNA length, structure, and modifications; bioinformatics etc), I would like to take the opportunity here to point out the potential for RNAi Therapeutics that include a immune-regulatory element. Moreover, as this is typically related to the uptake of the RNAi formulation in cells other than the primary target cells, I would also like to make us consider the potential for RNAi Therapeutics exploiting the entire biodistribution of a particular RNAi drug delivery system.

When we think about indications such as cancer and viral infections, the importance of the immune system in eliminating the disease cannot be underestimated. Cytokine therapies e.g. are well known to these areas of medicine and it is no coincidence that there have been long-standing efforts in harnessing the ability of nucleic acids to induce TLR and other immune signaling pathways to improve both cellular and humoral immune responses.

It is therefore conceivable that an immuno-stimulatory siRNA is not necessarily screened out during the siRNA selection process, but is deliberately packaged into a nanoparticle which in addition to the primary target cells (cancer cell, virus infected cell, etc.) would also be taken up by phagocytic cells where the cytokine stimulation would lead to enhanced antigen presentation or the augmentation of monoclonal antibody therapies. To further take full advantage of the biodistribution of the RNAi formulation, the RNAi drug could also contain two or more different siRNAs, each one designed to knock down a suitable gene in the various cell types that the nanoparticle is taken up in (e.g. in the case of a liver delivery system that enters both Kupffer cells and hepatocytes, an siRNA against a immuno-regulatory gene expressed in the Kupffer cells and maybe other phagocytes and one siRNA for a hepatocyte-specific gene).

In addition to immune-stimulation, certain siRNA formulations could be used for concomitant gene knockdown and immune suppression. As work by Protiva (now Tekmira) has shown, siRNA modifications may not only be used to avoid unwanted TLR signaling through siRNAs, but to inhibit these TLR responses in trans. A single modified siRNA could thus be employed in a two-pronged gene knockdown/TLR signaling inhibition strategy for treating autoimmune disorders.

Based on the acquisition of prior TLR company Coley by Pfizer, Alnylam’s vaccine spin-off intentions, and Tekmira’s IP and know-how on the immunological properties of nucleic acids, I would not be surprised if we should be hearing relatively soon more about such multi-functional RNAi Therapeutics.

Rather than considering innate immune responses and imperfect biodistribution as nuisances, it may well turn out that a number of RNAi Therapeutics may get the extra bit of efficacy out of simultaneously modulating immune responses and knocking down genes in multiple cell types. In my opinion, the medical and commercial opportunities for that are currently underappreciated.


Anonymous said...

If you refresh yourself with the January 2007 Tekmira-Alnylam alliance, Tekmira acquired global exclusive rights from Alnylam to certain siRNA immunostimulatory IP. Tekmira had long understood that certain DNA and RNA sequences, encapsulated and delivered in its lipid systems, could be important TLR therapeutics. Plus, certain other therapeutic areas (antiviral in particular) could have breakthrough products which silence a gene to kill the virus, and/or induce an immume response to either kill or create a vaccine-like effect.

Dirk Haussecker said...

Totally agree.

Anonymous said...

Most interesting post, as always.

Speaking of Pfizer/Coley, do you know what is the IP background of their RNAi therapeutics ambition? Unless I am missing something, it would appear that they will eventually need to strike some sort of a licensing arrangement with Alnylam (and/or Merck or RXi as Tuschl I coexclusive licensees), depending on how the pending patent contests go.


Dirk Haussecker said...

Martin- I think the rational of Pfizer in re-modelling Coley as an RNAi Therapeutics development arm is in their expertise in oligonucleotide medicines in general and their interaction with the immune system in particular. Important know-how, and maybe already some related IP. Furthermore, I agree with Dr. Krieg's comment that there is still lots of potential for creating valuable RNAi Therapeutics-related IP, particularly with the wide reach of a Pfizer, but that does not mean that much of the core RNAi trigger structure and chemistry IP is already claimed.

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