Sunday, May 11, 2008

Alternate Use of Two SiRNAs for Chronic RNAi Therapeutics

First, I wanted to write about the pros and cons of developing RNAi Therapeutics as antivirals, or the use of dual-acting siRNA agents, but then decided to sacrifice what remains of my credibility and propose a somewhat unorthodox method to manage off-targeting in RNAi Therapeutics for chronic medication.

As discussed before, both bioinformatics and gene profiling technologies can be applied in the selection of candidate siRNAs with the least likely adverse off-targeting effects. Bioinformatics may avoid sequence elements that occur at high frequencies in mRNAs or in a particular unwanted genes, while microarray profiling may experimentally pick out those genes which are downregulated at least on the RNA level which, despite some caveats, is still a pretty good predictor of off-targeting (note that potentially even more predictive protein mass-spec techniques may also be applied soon for off-targeting). In that manner, it is possible for Merck, for example, to screen out those siRNAs which off-target numerous genes or those genes that you would rather leave untouched. Finally, chemical siRNA modifications may allow for the general reduction in the number off-target interactions.

Still, with all of this in hand, off-target risk remains. Due to the redundancy of the genetic code, it should be generally easier to translate into humans off-target phenotypes from preclinical models for protein-targeting drugs than for RNA knockdown therapeutics. That means, a given drug is more likely to still interact with the same homologous protein in different species because the overall function and therefore usually shape of a protein is more conserved than the underlying mRNA sequence, while even a slight nucleic acid change at even a single position may decide whether an mRNA is an off-target for an siRNA or not at all. So what may be true for off-targeting even in a non-human primate may look quite different in man.

Off-targeting should be a concern particularly for chronic applications of RNAi Therapeutics. A 50% reduction in an important gene due to an siRNA for hypercholesterolemia for example may eventually manifest itself as an off-target toxicity following prolonged drug use. While this is true for essentially any class of drugs, RNAi Therapeutics may have an advantage. Because siRNAs as a class are quite homogenous in terms of pharmacological properties, how about entering two siRNAs targeting the same gene into the clinic, as a single drug development program, but whereby the siRNAs are given alternately?

This would be somewhat similar to how siRNA cocktails are considered for cancer and antiviral RNAi, but with a different rationale, or the idea behind Dharmacon’s smartpools. Just change the siRNA and leave the rest the same, including the delivery formulation. Similar to food where it’s better to consume a varied diet than constantly eat a single healthy dish, that way the siRNA would be changed before an off-target had the chance to manifest itself without having to take a drug holiday. That way, the fact that, unlike protein-targeting therapeutics, two siRNAs even for the same target have completely different off-target spectra, could be turned into an advantage.

I’m not sure how well this would go down with the increasingly defensive FDA, but maybe they could make a start and be more open-minded when it comes to new technologies.

PS: Another advantage of RNA knockdown therapeutics versus protein therapeutics is that it’s much easier to measure changes in RNA and protein abundance (RNA therapeutics) than determine drug-host interactions and their potential consequences, which in the case of RNA therapeutics, as a class, should be quite predictable while they should differ much more widely in the case of say small molecules.


Anonymous said...

Hi Dirk

excuse an off-topic question and one that demonstrates my scientific ignorance but perhaps you will educate me on the following:

Delivery of RNAi trigger into the right tissue is clearly the limiting factor for therapeutical applications of RNAi (and I understand that SNALPs with the ability to deliver siRNA into the liver and certain other issues represent a significant but only relatively recent progress on the front of systemic delivery). Now, judging from the impressive pipeline of antisense drugs that ISIS and its licensees have in clinical trials, the systemic delivery of single stranded antisense RNAs must be in a far more advanced stage compared to the systemic delivery of siRNAs. My question is what systemic delivery technology does ISIS (and other antisense companies) use for its antisense drugs and why cannot the same delivery technology be used for siRNAs?



Dirk Haussecker said...

Thanks for the question, Martin. I've tried to address the issue in the May 17 entry. Hope that helps,

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