Sunday, January 26, 2014

Silence Therapeutics DACC Lipoplexes for Lung Endothelial RNAi Delivery

After having shown for some time now deep and long-lasting gene knockdown in lung endothelial cells, Silence Therapeutics has finally published (Fehring et al. 2014) more detailed chemical and pharmacokinetic information on the DACC formulation.  This formulation could be useful for indications such as cancer involving the lung and acute lung injury.

Chemistry: cholesterol replaces helper phospholipid DPhyPE

Atuplex has long been the workhorse delivery technology of Silence Therapeutics.  Atuplex has been shown to target pretty much all vascular endothelial cells independent of tissue/organ system and enables the company's lead candidate, Atu027 for the prevention of cancer metastasis currently in phase Ib/IIa in combination with gemcitabine in pancreatic cancer.  Unlike the four-lipid formulation pioneered by Tekmira, Atuplex consists of just three lipids:

-          the cationic lipid AtuFECT01 for cell attachment and penetration (proprietary);
-          a pegylated lipid to prevent aggregation;
-          and the helper phospholipid DPhyPE for structural stability.

To my surprise, the DACC formulation contains the same cationic and pegylated lipids as Atuplex.  The main difference is in replacing the helper phospholipid DPhyPE with another helper lipid, in this case cholesterol.  With this change (and some adjustments in the lipid ratios), 40% of the DACC ends up in the lung with the concomitant silencing of genes in resident endothelial cells.

Silence Therapeutics’ strategy of utilizing a given cationic lipid in new lipid combinations therefore stands in contrast to previous efforts by the likes of Tekmira and Dicerna which have focused on the discovery of new cationic lipids to increase potency and the therapeutic index.

Rationale of DACC over Atuplex for lung endothelial RNAi not fleshed out

Although the new research clearly shows that the lung is the most important physical sink for DACC, the study did not investigate whether this translates into a tissue-specific knockdown effect as well [correction 28Jan14: Figure 4 of the paper does show preferential knockdown in endothelial cells of the lung versus other tissues].  This would be an important additional safety-related rationale for using DACC over Atuplex for lung endothelial gene knockdown, especially for target genes that might have critical functions in normal physiology as well. 

Atuplex, in contrast, has previously been shown to mediate lung endothelial gene knockdown, not just in mice (as DACC in this study), but also non-human primates.  What is more, the previous Atuplex studies showed comparable (~70-80%) knockdowns at ~10-fold reduced dosages (0.3mg/kg vs 2.8mg/kg).  It will therefore be important to test whether lower dosages are feasible for DACC knockdown in non-human primates, potentially with the use of slow infusions instead of bolus injections as was the preferred method in the present study.  And as is my pet peeve when it comes to Silence’s delivery technologies, why not attempt them with other, non-AtuRNAi trigger technologies when a factor of 2 could make all the difference in whether you have an acceptable therapeutic window or not.   

It should be noted, however, that unlike Atuplex, DACC appears to have a more reliable dose-response and seems to be tolerated at up to 6mg/kg so I trust that Silence has good reasons for choosing DACC for programs such as acute lung injuries (ALI). Based on the data revealed by the company thus far, it appears that the ALI candidate Atu111 is the prime candidate to be Silence's next clinical development candidate.

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By Dirk Haussecker. All rights reserved.

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