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DRACO antiviral

Discussion in 'Antivirals, Antibiotics and Immune Modulators' started by RYO, May 22, 2014.

  1. RYO

    RYO

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    Does anyone know of any new information about DRACO. Dr. Todd Rider has DRACO fund facebook page. Hopefully, he will organize crowd funding. I think CFS/ME community should support his research.

    DRACO - Double-stranded RNA (dsRNA) Activated Caspase Oligomerizer

    http://www.plosone.org/article/info:doi/10.1371/journal.pone.0022572

    www.youtube.com/watch?v=TQhb1P3sMVs
     
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  2. Hip

    Hip Senior Member

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    On this DRACO funding website, Dr Todd Rider states that:
    If DRACO works against the enteroviruses and herpes family viruses that are linked to ME/CFS, and thereby cures or improves ME/CFS, then with 17 million patients ME/CFS worldwide, this should demonstrate that DRACO is effective against viruses of commercial interest. This figure is comparable with the 35 million people living with HIV/AIDS worldwide.
     
    Last edited: May 28, 2014
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  3. RYO

    RYO

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    Is there anyone out there with knowledge and experience about how to start crowdfunding?
     
  4. RYO

    RYO

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    Or how about individuals with a million dollars to spare?
     
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  5. RYO

    RYO

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    Unfortunately, I doubt a major pharmaceutical company will step forward to invest in research to see whether a novel antiviral may help patients with CFS / ME. It would more feasible if a CFS / ME organization raised funds, then approached Dr. Rider with specific request to test antiviral on CFS / ME patients. If we could get to this point, then I think we have enough clinicians who could design double blinded placebo controlled study.
     
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  6. Hip

    Hip Senior Member

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    What about multiple sclerosis patients, a disease strongly linked to Epstein-Barr virus? Some researchers believe that MS will be eradicated once an EBV vaccine is finally developed. In the mean time, DRACO might be very beneficial for MS.
     
  7. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    is draco an antiviral or an immune mod type drug similar to ampligen??
    Cant quite get my head around how it works, any other links to it??
     
  8. Hip

    Hip Senior Member

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    The way DRACO works is this: most viruses produce double stranded RNA (dsRNA) inside human cells when they infect a cell. Furthermore, this dsRNA only appears in cells when there is a viral infection. Therefore dsRNA is almost the perfect marker for viral infection of a cell.

    The DRACO drug simply consists of a protein that is attracted to the dsRNA, with this protein being attached to a second protein that is designed to make the cell commit suicide (apoptosis). So the DRACO drug will only be drawn into the virally infected cells, and selectively cause them to commit suicide. More details here.

    Crucially for ME/CFS, DRACO should also work on the non cytopathic enterovirus infections inside cells, which Dr Chia and others think may be driving this disease, because these non cytopathic enteroviruses actually comprise dsRNA.

    The only consideration I can see is whether DRACO might kill too many cells, if an ME/CFS patient has a very widespread infection. But that is an issue for the experts to examine.
     
    Last edited: May 26, 2014
  9. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    Does it have an effect on herpes viruses. Im thinking that many of us probably have multiple viruses on top of enteroviruses too, could be a big die off type thing?? Sounds interesting. I wonder if treating them first with antivirals and immune mods would help reduce the amount of infected cells before using draco???
     
  10. Hip

    Hip Senior Member

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    I believe so. DRACO is a universal antiviral, acting against every virus which produces dsRNA in infected cells, which nearly all viruses do.
     
  11. RYO

    RYO

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    I think others on previous posts have raised concerns about how DRACO may kill off too many cells. I am not sure if there are any animal models that would test that theory. I have read that researchers study Hep C in mice. One study design could look at effects of different doses of DRACO. I also wonder if the "entry" molecule could be altered to target specific tissue types. Lastly, I am hopeful that patients with CFS / ME will be able to tolerate DRACO in the same way that cancer patients tolerate toxic chemotherapy.

    I doubt using antivirals or immune mods will reduce amount of infected cells. If the theory is true that the non cytopathic enterovirus is the driving factor in CFS / ME, the problem with antiviral and immune mods is that they fail at ridding the body of infected cells. It may also be the reason why that patients treated with rituximab improve but eventually relapse. Rituximab decreases B cells but the agent that is triggering abnormal immune response remains.

    I wonder if a PET scan could be used to first determine what the viral cell burden is by replacing capase oligomerizer with a radiotracer similar to molecular imaging technologies being developed to diagnose Alzheimer's disease.
     
  12. Hip

    Hip Senior Member

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    Immunomodulators will fight off noncytopathic enteroviruses in infected cells if the immunomodulator raises type I interferons (like interferon alpha or beta). These interferons specifically target viral dsRNA.

    The interferon immune response is triggered by the presence of viral dsRNA inside a cell. Toll-like receptor 3 (TLR3) is the cell's detector of viral dsRNA, and when this detector is triggered by dsRNA from a viral infection in the cell, it causes interferon to be released. Interferon in turn causes RNase L to be released, and this is the factor that destroys the virus in the cell.

    In summary:

    viral dsRNA within a cell ➤ triggers TLR3 ➤ releases IFN ➤ releases RNase L

    RNase L destroys the single stranded viral RNA inside the cell, without necessarily destroying the cell. Though type I interferons can also promote cell suicide of infected cells too. More info about noncytopathic enteroviruses and interferon in this post.



    As an aside: it occurred to me that one could develop a drug similar to DRACO that was more gentle on infected cells. It would work like this: rather than join a cell suicide-triggering protein to a protein that is attracted to the dsRNA, as you have with DRACO, you might instead join interferon alpha to the protein that is attracted to the dsRNA.

    With such an interferon-based DRACO-type drug, the interferon alpha would selectively gravitate towards the virally infected cells that contain dsRNA, and thus perhaps fight off the virus within these cells without necessarily killing the cell. Such an interferon-based drug would also create a highly targeted form of interferon alpha therapy, that does not affect healthy cells, just virally infected cells (and so might eliminate the side effects of interferon therapy, such as severe depression).

    A variation on this theme might be to join the drug Ampligen to the protein that is attracted to the viral dsRNA. Ampligen is an interferon inducer (it works by triggering TLR3). Again, that way, Ampligen would only be delivered to the virally infected cells containing dsRNA, and not into healthy cells. This might make Ampligen more effective, and reduce its side effects.

    Whether such variations on DRACO are technically possible, though, I am not sure.
     
    Last edited: Nov 4, 2014
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  13. RYO

    RYO

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    Yes, I agree and understand how interferons should work. However, Dr. Chia has treated patients in the past in interferon gamma with short term success but eventual relapse. I have personally taken interferon B for 6 months leading to modest recovery but again relapse. The treatment of chronic hepatitis C infections with pegylated interferons and ribavirin certainly speaks to lack of efficacy. New hepatitis C drugs - RNA polymerase and NS5A inhibitors can have 90% eradication rate. I should clarify my statement. I believe currently available immunomodulators for enteroviral infections lack efficacy.

    This is an article about Coxsackie virus subtype 3. I am not sure it would apply to other subtypes.

    The Coxsackievirus B 3Cpro Protease Cleaves MAVS and TRIF to Attenuate Host Type I Interferon and Apoptotic Signaling

    "Several viruses have evolved sophisticated mechanisms to attenuate antiviral host signaling by directly interfering with the activation and/or downstream signaling events associated with PRR signal propagation. Here we show that the 3Cpro cysteine protease of coxsackievirus B3 (CVB3) cleaves the innate immune adaptor molecules mitochondrial antiviral signaling protein (MAVS) and Toll/IL-1 receptor domain-containing adaptor inducing interferon-beta (TRIF) as a mechanism to escape host immunity."


    I doubt a large pharmaceutical company such as Gilead would invest in developing antivirals for enteroviruses. This points to one of the most important dilemmas in CFS / ME. We do not have enough ways the objectively diagnosis this disease. Larger studies that are reproducible are needed to prove or disprove link between chronic viral infections and CFS / ME. All we have now is the "smoking gun".
     
  14. Hip

    Hip Senior Member

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    That's an interesting paper. I just found found the following study in which they developed an experimental coxsackie B virus 3C protease inhibitor by modifying an existing drug AG7088 (Rupintrivir), which is an inhibitor of rhinovirus 3C protease:

     
  15. RYO

    RYO

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    At the end of the article, it states, "CVB3 3CPI could be used as a potential novel therapeutic agent for the treatment of acute human viral myocarditis during the viremic phase." Unclear what effect if any it could have on non cytocylytic enteroviral infection.

    I recently read "old" update from Chronic Fatigue Initiative. Dr. Lipkin was not able to find any clear evidence of viruses in blood samples of CFS patients. Someone alluded he may perform further research studying the gut of CFS patients (studying stool samples). Hopefully, he will study tissue samples as well (gut, muscle, nervous tissue).

    It is clearly of matter of conjecture that a drug like DRACO with cause severe tissue damage due to triggering apoptosis in CFS/ME patients. We can't assume that the myriad of symptoms in CFS/ME necessarily means large number of cells are affected/infected.

    If DRACO ever became available for human trials, it would interesting from a diagnostic perspective. What if DRACO had no effect on CFS/ME patients. That would imply that our assumption that a "smouldering" viral trigger as cause of CFS/ME is flawed.

    However, it is my hope that a drug like DRACO can cure CFS/ME so that we can return to our lives. Not a day goes by that I look at casual jogger on the road without feeling a sense of loss. I use to love running on trails with my dog or just taking a long walk in the woods. I found out my dog gained 7 lbs since I got sick.
     
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  16. Hip

    Hip Senior Member

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    It's quite possible that the cognitive and autonomic symptoms of ME/CFS do indeed result from a very small number of infected cells in the brain and/or the autonomic nervous system.

    Have you read VanElzakker's paper on the vagus nerve infection hypothesis of ME/CFS — it's one of the most promising new etiological theories of ME/CFS so far proposed. VanElzakker explains that the inflammatory cytokines IL-1β, TNF-α and IL-6 that are released during infection serve to instigate sickness behavior. The vagus nerve possess sensors for these cytokines, and this nerve is designed to trigger sickness behavior in the brain when it detects these cytokines within the body. In other words, it is the job of the vagus to detect when you are ill with an infection, and to instigate appropriate behavioral responses in the brain in order that you rest and deal with this infection. The interesting thing is that sickness behavior symptoms are very similar to those of ME/CFS.

    VanElzakker says that if you have a chronic low-level infection within the vagus nerve itself, then the vagus will be constantly activated by these cytokines. And because in a vagus infection, these cytokines are produced within the nerve itself, due to this close proximity of production, even low levels of these cytokines will cause a high activation of this nerve. VanElzakker proposes that a chronic low-level infection within the vagus will continually trigger sickness behavior, and that this is the basis of ME/CFS.

    One of the significances of VanElzakker's rather beautiful theory of ME/CFS is that it only takes a very small local infection within the vagus nerve to produce a major effect.


    Provided DRACO can cross the blood-brain barrier so as to be able to target brain and autonomic nerve infections (this DRACO paper suggests that it should be able to cross the BBB), then I think it stands a good chance of being very helpful if not curative for ME/CFS.
     
    Last edited: May 29, 2014
  17. Hip

    Hip Senior Member

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    I wonder whether a more direct targeting of the brain by antivirals might work in ME/CFS. For example, this study found that "intranasal administration of interferon beta resulted in significant delivery throughout the CNS and cervical lymph nodes with low delivery to peripheral organs."

    So intranasal interferon might be more helpful for ME/CFS patients. And it could more economical on expensive interferon, since less interferon is delivered to the peripheral organs, and more is delivered to the brain.

    Other antiviral drugs might also be taken intranasally.
     
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  18. RYO

    RYO

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    Yes, I read about VanElzakker's paper. I thought it was especially interesting considering my unusual symptoms when I first became ill. As with many other CFS / ME patients, my disease started with a sudden severe viral illness. I first developed splitting headache, flu like myalgias (especially in my legs), sore throat and gastrointestinal symptoms (nausea, anorexia, and epigastric pain). I was hospitalized a month after my initial illness because I had the worse chest pain of my life. I literally thought I was going to die on the way to the hospital. I usually have very high pain threshold. During my hospitalization, I had periodic waves of what felt like catecholamine surge. My heart rate was racing, I experienced whole body flushing sensation, and my left arm turned white and cold to touch. It was the most bizarre experience of my life. It lasted about 2-3 days. I had to call a nurse 2 AM in the morning to touch my left arm because I didn't think anyone would believe my symptoms unless they saw and touched my arm. The doctors didn't know what caused it. They later implied it may have been anxiety by treating me with alprazolam.

    Later when I got home, I had time to reflect on my symptoms. I suspected then that there was a connection between my gut and autonomic dysfunction. I believe the portal of entry of the virus (likely enterovirus) was my stomach. Once it got past "GI barrier", it spread to my vagus nerve traveling up to the heart and beyond.

    I feel fortunate that my "brain fog" is not very severe. However, Iike many others, my sleep patterns severely disrupted.

    After 18 months, I was actually doing fairly well. I was able to manage going back to work in the afternoons for 4-5 hours. My relapse came after getting viral gastroenteritis. I was on my second round of Betaseron. I was taking Equilabrant at the same time. Neither was able to prevent the episode of viral gastroenteritis. It sounds like Dr. Lipkin is on the right track by pursuing "the gut". Perhaps the viral gastroenteritis triggered release of inflammatory cytokines or it caused "immune stress" to tilt the balance towards "vagal dysfunction".

    This may be also be part of the reason why we all experience PEM.

    Cardiac vagal control before, during and after exercise
    J. H. Coote a1 and Valerie F. Bothams a1
    a1 Department of Physiology, Medical Sciences, The University of Birmingham, Birmingham B15 2TT, UK
    Abstract

    There is much evidence showing that the rapid rise in heart rate at the onset of exercise is due to a withdrawal of cardiac vagal tone. This short review discusses the main afferent mechanisms involved in this effect. In addition to signals from central motor command it is shown that muscle mechanoreceptors of group III afferent fibres also play a significant role. Recent studies in man demonstrating this by stretching muscles such as the triceps surae or by direct compression of muscles are briefly reviewed. The evidence also supports the idea that these small fibre mechanoreceptors inhibit the baroreceptor-heart rate reflex. Several studies suggest that skeletal muscle metaboreceptors (mainly group IV) are more important for increasing cardiac sympathetic and vasoconstrictor nerve activity. At the conclusion of exercise the cessation of mechanoreceptor stimulation is an important factor in determining the rapid return of heart rate to resting level.

    Experimental Physiology (2001) 86.6, 811-815.

    Perhaps exercise influences vagal tone and triggers release of inflammatory cytokines. For some of us, that may be the simple act of standing. It makes me wonder if there was a way to modulate vagal tone, it may lead to at least "Band-aid" treatment.

    Hip - thank you for your responses. I don't know about you but these discussions for me are therapeutic.
     
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  19. Waverunner

    Waverunner Senior Member

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    DRACO would be very interesting. The same is true for all other antivirals. Last year a study was published, which stated, that a viral infection was highly correlated with IBD. The infection may even be causative. The problem we face is, that we lack the antiviral drugs to test these findings. In my eyes, the whole drug approval and development field is completely broken. It takes 12-15 years and costs 800 million to 5 billion dollars to get a drug approved. No scientist can afford to get his drug approved. Patients and PWCs are completely out of the picture. If any PWC wanted to try a new drug and even would take all the consequences (including a fatal outcome) he would no bet allowed to. So the whole CFS tragedy keeps continuing. No innovation, nothing. PWCs are too weak to fight or raise their voices, so no pressure is put on politicians or pharma to change anything.

    If you want a realistic perspective, chances are very low, that any CFS drug will be released within the next 20 years, which means, that many PWCs will be dead before this illness can be treated/cured. The only chance I see is whole genome sequencing (WGS) and gene therapy. Find out what mutations drive CFS and cure them with gene therapy. We already have the tools for both problems. WGS gets cheaper and better every year and great findings have been made in gene therapy as well (e.g. CRISPR). I think we, as CFS community, should slowly start to realize, that nobody will help us, if we don't help ourselves.
     
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  20. RYO

    RYO

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    I completely agree with you that the chances are very low that a CFS drug will be released within next 20 years. I posted a thread about a NYTimes article about how many good scientists "are hitting the streets" because of declining NIH funding. In my opinion, one of the few slim chances we have is to draw the attention of sympathetic philanthropist who can invest in CFS research or perhaps venture capitalists. There are several examples of medical research funded by small well endowed groups that lead to breakthroughs that probably could not have been achieved without motivated private funding. Perhaps I am also underestimating the power of crowd funding. Laura Hillenbrand is the most famous person that I know of that struggles with CFS / ME.

    I finished reading VanElzakker's paper last night. It suggests some interesting potential treatments such as glial inhibitors such as ibudilast. It has been used in Japan for 20 years to help treat asthma patients and it has good safety profile. If it was determined that this medication can at least ameliorate some of our symptoms, we can recover enough function so the wait for ultimate cure won't seem endless.

    Let's also get some perspective here. I live with symptoms of CFS everyday. But I also know friends and family members who struggle or died from with such diseases as ovarian cancer, prostate cancer, ALS, Parkinson's disease, diabetes, and breast cancer. We should remain positive and learn from others who have suffered about to how to raise awareness about their disease and contribute to meaningful research. How many cancer patients dream about a cure before it's too late.

    To your second point, I wholeheartedly agree that genomic medicine may help explain and treat CFS. It certainly deserves as much attention as antivirals.

    I am certainly "all in" for helping ourselves and not just waiting for a miracle. Someone more eloquent once used the phrase "sober enthusiasm".
     
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