Tuesday, June 19, 2012
Friday, June 15, 2012
- The target genes (PHD enzymes) are cell-autonomous negative regulators of the expression of a secreted factor (here: erythropoietin/Epo). This means that even if efficient RNAi knockdown were only achieved in a subset of cells, the secreted factor that will be generated in this subset of cells can still act globally through the systemic circulation. This is in contrast to other gene targets, such as certain intracellular targets involved in cancer cell proliferation, where efficient gene knockdown would be required in almost every cell to achieve a measurable outcome.
- Specific multi-targeting. In order to exploit a genetically intriguing mechanism for the treatment of disease (PHD regulation for the treatment of anemia), it was necessary to simultaneously knock down three gene family members. Small molecule inhibitors with such multi-targeting activity would most likely cross-react with additional family members, increasing the risk of (A) obtaining confounding biological outcomes as other family members are more likely to play roles in related biological pathways than e.g. a spurious RNAi off-target event that is pathway-independent, and, of course, of (B) off-target toxicity. The next time you hear about that exciting multi-targeting kinase inhibitor approach in oncology, remember that many of these were not multi-targeting by design and that there will be a number of additional kinases being hit that you will hardly hear about. In summary, it is not just the capacity of RNAi Therapeutics for multi-targeting (e.g. as in the clinical candidates ALN-VSP02, TKM-EBOLA), but it is also the more ‘wholesome’ multi-targeting mechanism that is an advantage of the technology here.
- Tissue-specific delivery (here: SNALP and liver). Non-specific, but also specific targeting when it occurs in the wrong tissues, may cause toxicities. In this example, because the gene family to which the target genes (PHD enzymes) belong play roles in various non-targeted biological processes throughout the body, there is great concern that a small molecule PHD inhibitor would cause a number of toxicities. With regard to on-target toxicity in the wrong tissues, the HIF transcription factor that is regulated by the PHD1-3 enzymes plays an important role in cancer biology and inhibiting it all over the body may elevate the risk of developing cancer. On the other hand, with the SNALP-formulated PHD siRNAs most of the knockdown can be directed at the desired liver so that the numerous on- and off-target toxicities in the rest of the body become irrelevant.
- Being an exclusively intracellular target means that it is not druggable by monoclonal antibodies = less competition.
- Recombinant protein therapy (e.g. rhEpo) often involves periods of supraphysiologic exposures which can be associated with adverse events (this is thought to be one problem with rhEpo therapy). By contrast, (genetic) PHD knockdown allows for more physiologic regulation of the targeted biological pathway making it a potentially safer and also more efficacious therapy. This advantage of affecting a more physiologic pathway compared to the competing recombinant protein approach is largely the result of having a larger target space to choose from.
Friday, June 8, 2012
Wednesday, June 6, 2012
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