old myth of curing hepc with antisense, page-38

For the record, I approve of curis asking these questions. He is perfectly entitled to do so, and I'm perfectly happy to answer these sorts of questions.

curis - I'm not going to touch on whether now is the time to buy, or drug-specific costs, as I suspect others will do so. I'll instead discuss why ddRNAi is the option I'm willing to put my money on, and why I consider it a better approach than traditional therapies or other oligonucleotide-based approaches, including antisense.

First and foremost, it should be noted that the problem of viral resistance to drugs is actually a significant issue when dealing with oligonucleotide-based treatments. This is because a single base change in a gene is often enough to confer resistance to RNAi-mediated inhibition. Viral resistance to classic antiviral treatments, by contrast, requires that the virus mutate in a manner which alters the target protein in a way which prevents the drug from interacting with it effectively but allowing it to function nominally.

This was the case with ISIS's ISIS-14803, which targeted only one region of the HCV genome - IRES. Comparatively, Benitec's TT-034 targets three distinct and highly-conserved regions of the HCV genome to mitigate the potential for treatment-selected resistance - each of which can confer antiviral activity. This is similar to methods currently used with anti-retroviral drugs against HIV.

If this leaves you wondering why we don't just stick to doing the same with "antisense" oligonucleotides, or even traditional protein-targeting therapies like sofosbuvir, it's due to a rather interesting manner in which a host cell protein called "Dicer" interacts with shRNA oligonucleotides - "cleaving" at nonspecific points and generating a significant degree of diversity among the subsequent ssRNA strands that are produced.

To compare this to antisense oligonucleotides, think of it as TT-034 effectively producing dozens of ISIS-14803-esque treatments, in vivo. Understandably, this confers a significant degree of resilience against viral resistance derived from genomic mutations - something which is not possible with traditional therapeutic drugs, and which would be prone to cause potentially life-threatening liver damage if it were attempted with antisense oligonucleotides.

If you would like to see the different target sequences observed in TT-034 treated cells which were investigated in BLT's most recent paper, they are available in the following excel document, "Diversity of ssRNA strands processed out of TT-034–encoded shRNA hairpins expressed in TT-034–treated Con1b HCV replicon cells as determined by Illumina pair-end small RNA sequencing": http://www.nature.com/mtna/journal/v3/n2/extref/mtna201373x4.xls

One last note - this barely touches on the range of issues, and I have simplified some aspects to save time/prevent confusion. I am, however, more than happy to explain areas in more detail if people are curious.

curis (and anyone else) - keep asking difficult questions. While people might call you downrampers or bash you, I personally prefer to have my investments questioned. It keeps us holders on our toes, and if people are able to raise valid concerns that I can't personally think of a compelling explanation for, that is certainly something that will make me reconsider my position. Reading posts by people with opinions in agreement with my own is not what I come to HC for. ;)