Interessante post op Yahoo.
Hif2a is expressed by some cancers as a means to promote key tumor promotion/growth functions: hypoxia and, angiogenesis, amongst many others, as well. ARWR states that 90%+ of all ccRCC Express this protein, and decided to test reducing the production of it in mice to see if it will affect the cancer, and it does, dramatically!
How does RNAi do this?
ARO HIF2a gets into the cytoplasm where the messenger RNA are created to produce it, finds the specific "instruction set" in each strand, and replaces it with, in essence, a "blank", so, no protein can be produced.
This happened over and over again as an overall effort to stop most of it being produced while the drug is still inside the cell. When the drug is eliminated, the KD stops, so, it's important to dose enough in quantity and frequency to continue the effects to get the desired sustained reduced amount of hif2a in the blood, thereby crippling the cancer's ability to grow/multiply, and, actually, cause tumor cell death.
Get a look at the last hif2a presentation from last year..compare the treated mice versus untreated. The difference is OUTSTANDING, and clearly effective.
Phase 1 trials might be VERY compelling to watch. Why?
Trials must be in patients that express hif2a, that means cancer patients,..healthy volunteers would not be applicable, so...
How would the market react to a hold placed on the trial by the CTI because a single/multi dose at a certain level of hif2a significantly reduced or stopped/reversed tumor growth, versus placebo patients, and wanted to give the placebo patients the drug, as well??
I think ARWR controls phase 1, and partners it off with that data, whi h I suspect, per above, can come MUCH earlier than expected...ARWR style.. single dose escalating and then onto multidosing at that level after proven safe for 7 days.
Just sayin....
Tumor's are organ specific, that's why they are treated differently.
Never-the-less, intracelluar ligands can get a trigger, without intercellular ligands to any organ in the body that has HIF2a expressed. That's not the question here. or the argument.
What IS the argument is that HIF2a for ccRCC is specificallly targetted to kidney tumors. Kidney tumors are kidney cells that are multiplying and reproducing as a malignancy. That's a fact.
Now, to your point, you can inject an organism with just a trigger and get some KD anywhere in the body that it finds HIF2a. This is actually part of ARWR's trigger proving ground, and eventually, ligand selection proving gorund, in the preclinical stage of development. All you have to do is to look at any of their preclinical papers to see this. The problem is that you need alot of drug because you are dosing the whole organism, and KD in any of the selected areas is minimal. I mean, really low - like 10%, max. Thats what happens when you deliver a trigger alone.
Other risks for trigger only delivery are potential toxicity, both near and long term. Each trigger is different. Some are highly toxic, and some aren't Some are very stable, and some are quite fragile and susceptible to the immune system. Very inefficient way to deliver the trigger, as the ultimate effect is going to be low, and, if in clinical trails, they would have to prove that there is no toxic buildup in any of the 78 human organs. That's 78 biopsies. 78.
To get maximum and optimized effect, you need to make sure that you target the organ tumor itself. It does nothing to spray the whole body with HIF2a, and have only 5% reach a ccRCC tumor, but, it does a great deal of benefit to target that organ tumor ONLY. It will find those kidney tumor cells wherever they are in the body, because they are looking, specifically, for ccRCC tumor cells, after injected. That makes the whole dose much more efficient and effective.
So, to conclude, HIF2a uses both intra and intercellular ligands for delivery, to target ccRCC, only. if they want to target lung cancer (which I do believe they will - the published preliminary data about it 2 years ago), they will use the same ligands that EnaC uses to deliver the triggers to lung tumor cells, efficiently. (and, for those who do not know, lung cancer is now the #1 killer of all cancers, with pancreatic cancer running in 2nd place).