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ARC-520 Hepatocyte Targeted Therapy / Powerful HBV Silencer by Arrowhead Reasearch
Hey everyone,
Following the press release, I took studyforhope suggestion and read the paper on this new therapy. There's a lot to read and understand but here is what I got from my first pass (below is the link for the paper).
1. The therapy interferes with the RNA of the viral proteins: HbsAg, HBV DNA, and HbeAg
2. The therapy has shown in mice and non-human primates to have a powerful effect on reducing HbsAg, HBV DNA, and HbeAg (numbers of 90%+ from a single dose)
3. More importantly Arrowhead has found a very efficient way to deliver 99% of the drug directly to Hepatocytes which was previously a big concern due to toxicity.
4. The hope of this therapy is to inhibit the viral proteins to help the immune system recover and build immunity.
5. Many safety markers had no increase for example ALT.
6. They hope to provide this as a monthly injection.
Seems very promising. Looking forward to discussion on this from the community.
http://www.nature.com/mt/journal/vaop/ncurrent/full/mt201331a.html
Following the press release, I took studyforhope suggestion and read the paper on this new therapy. There's a lot to read and understand but here is what I got from my first pass (below is the link for the paper).
1. The therapy interferes with the RNA of the viral proteins: HbsAg, HBV DNA, and HbeAg
2. The therapy has shown in mice and non-human primates to have a powerful effect on reducing HbsAg, HBV DNA, and HbeAg (numbers of 90%+ from a single dose)
3. More importantly Arrowhead has found a very efficient way to deliver 99% of the drug directly to Hepatocytes which was previously a big concern due to toxicity.
4. The hope of this therapy is to inhibit the viral proteins to help the immune system recover and build immunity.
5. Many safety markers had no increase for example ALT.
6. They hope to provide this as a monthly injection.
Seems very promising. Looking forward to discussion on this from the community.
http://www.nature.com/mt/journal/vaop/ncurrent/full/mt201331a.html
Best Answer
Another off topic thing I picked up on based on what you had brought up I believe about Myrcludex is the potential problen of developing antibodies to the therapy by our immune system. With ARC-250 they mentioned that they didn't see this or it didnt occur which is a good thing?
After reading it a few times. It seems like the major problem or challenge could be targeting HBV effectively without interfering with our own gene products.
They seemed to have narrowed it down to over 90% accuracy but not 100%. So it seems like there could be very adverse effects if it hits and silences our own genes from the mismatch at the terminal ebd but they believe that it's well tolerated?
As I was reading the paper I got the feeling that this could be a very powerful yet dangerous therapy.
They seemed to have narrowed it down to over 90% accuracy but not 100%. So it seems like there could be very adverse effects if it hits and silences our own genes from the mismatch at the terminal ebd but they believe that it's well tolerated?
As I was reading the paper I got the feeling that this could be a very powerful yet dangerous therapy.
Here is the sentence you need to focus on for this:
Canonical siRNAs are based on 19 nucleotides of complementary sequence, but mismatches at the terminal ends are generally well tolerated and have much less effect on the efficacy of the siRNA than internal mismatches.
Canonical siRNAs are based on 19 nucleotides of complementary sequence, but mismatches at the terminal ends are generally well tolerated and have much less effect on the efficacy of the siRNA than internal mismatches.
Ok , now for starters to focus on the critical problem areas of this approach:
Look at the high specificity and sequence sensitivity of the target area sequence in these RNAs, which is discussed at a specific place in the paper. They made a strong effort to identify genotype independent sequences, so that they will have a drug that is effective across all relevant genotypes.
Also, they deselected from all mRNA sequences that can be expected in the human genome, to reduce the risk of switching off one of our own gene products. Very good and thanks to the human genome project for making that possible.
So now what major problem could occur due to the sequence sensitivity of the target sequence as it is mentioned in quite detail?
We will, after discussing this question, move on to the next problem area.
Look at the high specificity and sequence sensitivity of the target area sequence in these RNAs, which is discussed at a specific place in the paper. They made a strong effort to identify genotype independent sequences, so that they will have a drug that is effective across all relevant genotypes.
Also, they deselected from all mRNA sequences that can be expected in the human genome, to reduce the risk of switching off one of our own gene products. Very good and thanks to the human genome project for making that possible.
So now what major problem could occur due to the sequence sensitivity of the target sequence as it is mentioned in quite detail?
We will, after discussing this question, move on to the next problem area.
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But the sentence that i outlined from the paper holds a much more likely pitfall to this therapy.
The target message RNA has to be a very precise sequence for the silencing to work. Thus any mutation in this sequence will tender the drug ineffective and unresponsive in the cell containing the mutated cccDNA. We must assume such mutations preexist and will give the respective HBV genome a selective advantage. It will spread quickly and repopulate the liver with therapy resistent progeny. No more supression, a happy virus and a drop in stock prices. Since there are so many places where it can mutate it will likely do so.
To see problem number 2 you need to go the place where they discuss the magnitude of the surface antigen suppression that can be expected.
In this context it needs to be mentioned that the replicor drug suppresses the antigen particle production by a factor better than 10000! fold. It is likely that a very high degree of surface antigen removal is necessary to remove the tcell tolerizing effect.
The famous idea, that a reduction under 500 units is sufficient to rekindle very likely does NOT apply in this setting. But this is complicated topic in itself.
The next problem that looms is not so apparent.
Consider the reason, why the precore mutant with elimination of the e antigen reduces the chance that the infected cell can be eliminated dramatically. It is the lack of the cytosolic processing of the e antigen carrying also the class I core epitopes through the proteasome to the MHC CLASS I presenting molecules on the hepatocte surface where the cd8+ CTL engage with their Cognate T cell receptors.
What would happen if the surface antigen production is shut down due to messenger RNA silencing? How can the now available surface antigen epitope specific cd8+ T cells come and recognize the infected cell? It is as if the critical markers of infection are now turned off.
The Replicor drug does not touch the primary sythesis of the surface antigen, it only blocks the formation of the globular structure on the ER membrane. Thus proteasome processing remains fully intact and effective. All the lights are on and the infected cell is visible to the searching cd8+ Tcells, resulting in targeted lysis and hyperintensive localized IFN gamma bursts, that clean up the neigborhood by noncytolytic cccDNA elimination.