NZ team reactivate research into DRACO (renamed VTose), the universal antiviral that could cure ME/CFS

gbells

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I read the VTos/DRACO critique and agree with them that there are two serious red flags (number 1 and 2 below) indicating that this won't be successful in humans.
  1. Proteins greater than 4 amino acids long aren't absorbed into cells. VTos is around 318 amino acids long (Caspase-3 size) so it seems it won't be absorbed into cells.
  2. It is a large protein and they are allergenic so you get into the possibility of developing dangerous immune reactions.
  3. Apoptosis of large numbers of cells may be worse than keeping them alive infected due to the loss of function (needs research).
https://www.openphilanthropy.org/informal-writeup-dracos-potential-antiviral-treatment
 
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I read the VTos/DRACO critique and agree with them that there are serious red flags indicating that this won't be successful in humans.
  1. Proteins greater than 4 amino acids long aren't absorbed into cells. VTos is around 318 amino acids long (Caspase-3 size) so it seems it won't be absorbed into cells.
  2. It is a large protein and they are allergenic so you get into the possibility of developing dangerous immune reactions.
Have you also seen my rebuttal to the OpenPhilanthropy.org critique?
https://forum.kimermed.co.nz/index....nthropyorgs-list-of-objections-against-draco/
 
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gbells

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I see. If you use protein transduction tags you can get them in. However, these proteins are big so I am still wary of the autoimmune responses. Has any research been done on that? Being able to cross the blood brain barrier is impressive. Also, PTTs don't target the noninfected cells so what happens to the drug in the cells where it isn't used? Is it degraded and excreted? Also, we need to see that it is absorbed in the other tissues. https://www.nature.com/articles/3301383.pdf?origin=ppub
 
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I see. If you use protein transduction tags you can get them in.
Yes.

However, these proteins are big so I am still wary of the autoimmune responses. Has any research been done on that? Being able to cross the blood brain barrier is impressive. Also, PTTs don't target the noninfected cells so what happens to the drug in the cells where it isn't used? Is it degraded and excreted? https://www.nature.com/articles/3301383.pdf?origin=ppub
Protein size shouldn't be an issue. Much larger proteins than this have been used successfully with transduction tags, and ~300 AAs is actually on the small side as cellular proteins go:

1600046417343.png

Fortunately, proteins such as PKR, Apaf-1, FADD and RNase L that were used as part of DRACOs are already present in eukaryotes. Even though only part of the proteins were used, those parts include active domains. Therefore, the chances of autoimmunity should be reduced. In practice, Rider reported no signs of autoimmunity or other toxic effects in mice.

Having said that, unwanted immune responses are a potential issue for any new drug, and it's certainly something we will watch for during in vivo and clinical trials.

Transduction tags actually target all cells they come into contact with, not just infected cells. They will also cross through the nuclear membrane, into the nucleus.

Transduction tags are peptides -- mini-proteins -- so they naturally degrade the same way that all peptides and proteins in the body do, through proteases and the like. Partly for this reason, they tend to be much less toxic than conventional small molecule drugs.
 
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gbells

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Are PTTs approved by the FDA for drug use or are they still experimental?

So basically it seems the PTTs don't have any antigens on them so they don't trigger an immune response seems to be what you are saying.

Well given that you are including Apaf-1 and FADD in the PTT then if you needed to perhaps you could also add DISC to get around the EBV blocking and trigger necroptosis. It's a clever work-around for the blocked checkpoints.

As long as you don't kill too many cells at once I don't think the apoptosis should be harmful. However, it will probably take a lot of treatment to work through the layers of years of infected cells. I've been infected for 11 years and my treatment is taking several months (although half of it are rest periods because the chemicals arrest growth during the period they are taken).

Also, is there anything to the concern that VTos might bind to small natural DNA fragments?

If you were to add DISC it should work and even cure ME.
 
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Are PTTs approved by the FDA for drug use or are they still experimental?
AFAIK, the FDA doesn't approve parts of drug compounds, only the whole thing.

Last I heard, there were something like 200 drugs using transduction tags of one kind or another, weaving their way through clinical trials.

So basically it seems the PTTs don't have any antigens on them so they don't trigger an immune response seems to be what you are saying.
Not as far as I'm aware. And if a particular tag by itself did end up causing an immune response, there are something like 1800 others to choose from.

Well given that you are including Apaf-1 and FADD in the PTT then if you needed to you could also add DISC to get around EBV resistance and trigger necroptosis.
DRACOs used either (part of) Apaf-1 or FADD, not both at the same time.

The FADD --> Procaspase-8 path involves DISC. Apaf-1 activates Procaspase-9, which doesn't. We don't want to trigger necroptosis, though (via CICD, etc), only apoptosis. If both Procaspase-8 and -9 are effectively and durably blocked by EBV, and if interfering with viral replication by having PKR or RNase L bind to viral dsRNA isn't enough to slow or reverse those blocks, then it should also be possible to use Caspase-3 as an effector domain, which would bypass both DISC and Caspase-9.

As long as you don't kill too many cells at once I don't think the apoptosis should be harmful. However, it will probably take a lot of treatment to work through the layers of years of infected cells. I've been infected for 11 years and my treatment is taking several months.
For most viruses, people and conditions, I agree that apoptosis should not be harmful. As I explain in this article about how the drug works, apoptosis is a completely normal and natural process:

https://forum.kimermed.co.nz/index.php?/topic/6-how-does-vtose-draco-work/

Rider's tests with mice confirmed this. However, we have identified potential corner cases where this may not be the case, which we plan to test for.
 
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gbells

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If both Procaspase-8 and -9 are effectively and durably blocked by EBV, and if interfering with viral replication by having PKR or RNase L bind to viral dsRNA isn't enough to slow or reverse those blocks, then it should also be possible to use Casepase-3 as an effector domain, which would bypass both DISC and Caspase-9.
Actually if the person is infected with HHV6 it will block caspase 3 and 8 so that pathway won't work.
Procaspase 9 goes into caspase 3 which would also be blocked by HHV6.

Is there any way you can attach TRIF to DRACO instead (RIP) and add some DISC? I think this would be an easy pathway to trigger necroptosis.

Why don't you want to trigger necroptosis (vs apoptosis)? Aren't they equivalent?
 
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Hip

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Why don't you want to trigger necroptosis (vs apoptosis)? Aren't they equivalent?
Necroptosis is thought to cause a strong pro-inflammatory response (via release of cytokines), whereas apoptosis does not. There is enough inflammation going on already in acute viral infections, so you wouldn't want to increase inflammation, especially in infections like the coronavirus-induced SARS, where the inflammation can kill.

The 1918 influenza H1N1 Spanish flu pandemic was another viral infection where the inflammatory cytokine storm killed a lot of people. And the 2009 H1N1 swine flu pandemic also killed people via cytokine storms.

So it does not seem like a good idea to use necroptosis when you can instead use apoptosis.
 

Hip

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Just a small correction here. Dr Rider is the one who tested and had success with 15 viruses. We are just getting started with VTose. We do plan to test against SARS-CoV-2, though, as you said.
Thanks, I've corrected the original post accordingly.

Great to see you on Phoenix Rising @Kimer Med!
 
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Is there any way you can attach TRIF to DRACO instead (RIP) and add some DISC? I think this would be an easy pathway to trigger necroptosis.
I don't know for sure, but I don't think so.

Why don't you want to trigger necroptosis (vs apoptosis)? Aren't they equivalent?
Necroptosis is programmed cell death that results in necrosis. Necrosis is a process where the cell membrane effectively lyses, spilling the interior of the cell into its surroundings. The result is seen by the immune system as a danger signal, so it's very immune-activating, inflammation-causing, and so on.

Apoptosis is a different form of programmed cell death, where the cell breaks into small, bubbled pieces, which can then be easily digested and absorbed by scavenger cells. Unlike necrosis, apoptosis does not trigger an immune response, so no inflammation, etc.

I like to think of necrosis as a cell "exploding," whereas apoptosis is a cell "imploding."
 

Hip

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@Kimer Med, what are your thoughts about using DRACO/VTose against chronic viral infections? I believe DRACO was initially conceived as a treatment for acute viral infections, and regarding chronic infections, Todd Rider's 2011 paper states:
More extensive trials are also needed to determine ... if DRACOs are useful against chronic viral infections without producing unacceptable levels of cell death in vivo.
As you know, there are also numerous chronic diseases which are linked to persistent viral infection in the body tissues, and I wonder if you have you thought about these diseases as possible targets for VTose treatment. This article lists some chronic diseases associated with viral infections.

Of course, since association does not automatically imply causation, though many chronic diseases are linked to persistent low-level viral infections, proving that the virus actually causes the disease, or plays a causal role, is difficult.

But if VTose could more-or-less eliminate the viral infections found in these diseases, and if these diseases were then cured or greatly improved as a result, that might kill two birds with one stone: both proving the virus plays a causal role, as well as finding a treatment for the disease.
 
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@Kimer Med, what are your thoughts about using DRACO/VTose against chronic viral infections?
The short answer is that we are working toward making VTose effective against chronic viral infections. There are a number of potential technical challenges on this front, though. As Rider said, we need to test.

As you know, there are also numerous chronic diseases which are linked to persistent viral infection in the body tissues, and I wonder if you have you thought about these diseases as possible targets for VTose treatment. This article lists some chronic diseases associated with viral infections.

Of course, since association does not automatically imply causation, though many chronic diseases are linked to persistent low-level viral infections, proving that the virus actually causes the disease, or plays a causal role, is difficult.

But if VTose could more-or-less eliminate the viral infections found in these diseases, and if these diseases were then cured or greatly improved as a result, that might kill two birds with one stone: both proving the virus plays a causal role, as well as finding a treatment for the disease.
My view is that elimination of viruses alone may well cure a certain subset of chronic diseases. However, in many cases, there's much more going on than just a viral infection. Eliminating an HPV infection won't cure cervical cancer, for example, even though it was the cause.

Another example is chronic, long-term inflammation, which can be triggered by viruses and causes its own massive collection of downstream effects--not the least of which is ME/CFS--but it doesn't always go away when the original trigger is removed. So, while eliminating the virus may be a necessary condition for wellness in some cases, it also may not be sufficient. OTOH, with the virus gone, other treatments that were only partially effective before may suddenly work a lot better.
 

gbells

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The short answer is that we are working toward making VTose effective against chronic viral infections. There are a number of potential technical challenges on this front, though. As Rider said, we need to test.



My view is that elimination of viruses alone may well cure a certain subset of chronic diseases. However, in many cases, there's much more going on than just a viral infection. Eliminating an HPV infection won't cure cervical cancer, for example, even though it was the cause.

Another example is chronic, long-term inflammation, which can be triggered by viruses and causes its own massive collection of downstream effects--not the least of which is ME/CFS--but it doesn't always go away when the original trigger is removed. So, while eliminating the virus may be a necessary condition for wellness in some cases, it also may not be sufficient. OTOH, with the virus gone, other treatments that were only partially effective before may suddenly work a lot better.
Drug development and approval takes 10 years on average.
 

gbells

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I did some more research on the DRACO approach. Neither FADD or Apaf will work because they hang up at Active caspase-3 blocking by HHV6. If you could introduce either a pro-caspase 7 or active caspase 7 it would trigger parp if you blocked Nf-kb which is upregulated by EBV (easy to do with turmeric). Both EBV and HHV6 are common chronic viruses. Can you attach a form of caspase 7 (pro or active) to the PKR protein instead of FADD/Apaf? That would fix.
 

MonkeyMan

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There's also the issue of over stimulation that you and I suffer from Hip. Anything I take daily causes insomnia anxiety racing thoughts etc. Dosing low makes no difference. Anti virals don't quite do that I must admit but I guess it depends on the immune reaction. It makes it hard to dose long term anyway when over stimulation is a huge problem. Not sure why we react that way I know it drives me mad. As I've only recently realised I have this problem with almost everything.
Interesting. I have the same problem!
 

gbells

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Interesting. I have the same problem!
It's basically excessive cytokine activation (aka a mild cytokine storm like in covid). You can decrease it by reducing the dose of the activators and using earthing. However, if you overdo it then you'll stop the immune response completely and won't make progress with apoptosis. I aim to keep immune response tolerable with strong pain management. If you are making progress eventually the body will clear out the infected cells and it will lessen with treatment.
 

godlovesatrier

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Exactly. Getting the balance is impossible. Believe me I've been trying for years. At first my body simply didn't get over stimulated. That ended 2 years in. For example ive veen on 9000mg of monolaurin a day for about 5 weeks. It's got to the stage now where it's keeping me awake for hours at night. Although it's also stopping crashes and making life bearable. I'll go down to 3000mg but as soon as I get a cold or have any life stress I'll have to go back up to 9000. Keeping up with the subtle immune changes is almost impossible.
 

MonkeyMan

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You can decrease it by reducing the dose of the activators and using earthing.
Thanks @gbells! - I'd never heard of earthing till I read your post, which inspired me to Google it. Earthing sounds very interesting. How much has it helped you? Have you tried a "grounding mat", and if so, how helpful or not has it been? (I live in an apartment and it's difficult to find somewhere outdoors I can walk barefoot).